Distinct Mechanisms Of Action Research Articles

Novel Aryl Thioamides Derivatives as Insect Growth Regulators Analogues against Spodoptera littoralis(Lepidoptera: Noctuidae): Design, Synthesis, Insecticidal Activity and Biochemical Impacts.

A significant reason for developing innovative insecticidal active agents is the exponential rise in resistance to traditional chemical pesticides. Exploring new classes of insecticidal compounds with distinct mechanisms of action is one way to address this difficulty. So that, novel aryl thioamides derivatives 3-15 has been synthesized viaone-pot, three-component reaction of aroyl chloride, ammonium thiocyanate, and aromatic amines in dry acetone. The newly synthesized compounds' structures were validated by various spectroscopic methods, including elemental analysis, 1H NMR, 13C NMR, and infrared spectroscopy. Under laboratory circumstances, the synthesized compounds showed good and broad-spectrum insecticidal activities toward S. littorali. When compared to other synthetic target compounds, 2,4-dichloro-N-[(3-fluorophenyl)carbamothioyl]benzamide 11, 2,4-dichloro-N-[(3-fluorophenyl)carbamothioyl]benzenecarbothioamide 13 showed good insecticidal activity, with 46.33 mg/L and LC50 values of 49.25 mg/L for 2nd instar larvae. Furthermore, the compound 3 was the least toxic in controlling the second and fourth instar larvae of S. littoralis on tomato leaves. Additionally, several histopathological and biochemical features of the some synthesized compounds under laboratory circumstances were also examined.

Tramadol/Diclofenac Fixed-Dose Combination for Acute Pain Management: Bioavailability Assessment of a Generic Product.

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50mg)/diclofenac sodium (50mg) fixed-dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open-label, randomized, single-dose, 2-period, 2-way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed-dose combination tablets with a 7-day washout period. Blood samples were collected up to 36hours after dosing for tramadol and 12hours for diclofenac and quantified using a validated liquid chromatography-tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration-time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%-125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice.

ABBV-319: a CD19–targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies

AbstractGlucocorticoids are key components of the current standard-of-care regimens (eg, R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab], and hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine]) for the treatment of B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. CD19 displays restricted expression in normal B cells and is upregulated in B-cell malignancies. ABBV-319 is a CD19–targeting antibody-drug conjugate engineered to reduce glucocorticoid-associated toxicities while possessing 3 distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of a glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced fragment crystallizable (Fc)–mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven antitumor activity against multiple malignant B-cell lines in vitro, as well as in cell line-derived xenografts and patient-derived xenografts (PDXs) in vivo. Remarkably, a single dose of ABBV-319 induced sustained tumor regression and enhanced antitumor activity compared with repeated dosing of systemic prednisolone at the maximum tolerated dose in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed antiproliferative activity in a subset of B-cell lymphoma cell lines through the inhibition of phosphoinositide 3-kinase signaling. Moreover, afucosylation of CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity, and this activity was maintained after conjugation with GRM payloads. Notably, ABBV-319 displayed superior efficacy compared with afucosylated CD19 mAb in human CD34+ peripheral blood mononuclear cell–engrafted NSG-tg(Hu-IL15) transgenic mice, demonstrating enhanced antitumor activity when multiple MOAs are enabled. ABBV-319 also showed durable antitumor activity across multiple B-cell lymphoma PDX models, including nongerminal center B-cell diffuse large B-cell lymphoma and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in the phase 1 clinical trial. This trial was registered at www.ClinicalTrials.gov as #NCT05512390.

Anticancer activity of 8-hydroxyquinoline-triphenylphosphine rhodium(III) complexes targeting mitophagy pathways

Metallodrugs exhibiting distinct mechanisms of action compared with cisplatin hold promise for overcoming cisplatin resistance and improving the efficacy of anticancer drugs. In this study, a new series of rhodium (Rh)(III) complexes containing tris(triphenylphosphine)rhodium(I) chloride [(TPP)3RhCl] (TPP = triphenylphosphine, TPP=O = triphenylphosphine oxide) and 8-hydroxyquinoline derivatives (H-XR1–H-XR4), namely [Rh(XR1)2(TPP)Cl]·(TPP=O) (Yulin Normal University-1a [YNU-1a]), [Rh(XR2)2(TPP)Cl] (YNU-1b), [Rh(XR3)2(TPP)Cl] (YNU-1c), and [Rh(XR4)2(TPP)Cl] (YNU-1d), was synthesized and characterized via X-ray diffraction, mass spectrometry and IR. The cytotoxicity of the compounds YNU-1a–YNU-1d in Hep-G2 and HCC1806 human cancer cell lines and normal HL-7702 cell line was evaluated. YNU-1c exhibited cytotoxicity and selectivity in HCC1806 cells (IC50 = 0.13 ± 0.06 μM, selectivity factor (SF) = 384.6). The compounds YNU-1b and YNU-1c, which were selected for mechanistic studies, induced the activation of apoptotic pathways and mitophagy. In addition, these compounds released cytochrome c, cleaved caspase-3/pro-caspase-3 and downregulated the levels of mitochondrial respiratory chain complexes I/IV (M1 and M4) and ATP. The compound YNU-1c, which was selected for in vivo experiments, exhibited tumor growth inhibition (58.9 %). Importantly, hematoxylin and eosin staining and TUNEL revealed that HCC1806 tumor tissues exhibited significant apoptotic characteristics. YNU-1a–YNU-1d compounds are promising drug candidates that can be used to overcome cisplatin resistance.

IJAZ-based approach to engineer lepidopteran pest resistance in multiple crop species.

The fall armyworm (FAW) poses a significant threat to global crop production. Here we showed that overexpression of jasmonate ZIM-domain (JAZ) protein GhJAZ24 confers resistance to cotton bollworm and FAW, while also causing sterility in transgenic cotton by recruiting TOPLESS and histone deacetylase 6. We identified the NGR motif of GhJAZ24 that recognizes and binds the aminopeptidase N receptor, enabling GhJAZ24 to enter cells and disrupt histone deacetylase 3, leading to cell death. To overcome plant sterility associated with GhJAZ24 overexpression, we developed iJAZ (i, induced), an approach involving damage-induced expression and a switch from intracellular to extracellular localization of GhJAZ24. iJAZ transgenic cotton maintained fertility and showed insecticidal activity against cotton bollworm and FAW. In addition, iJAZ transgenic rice, maize and tobacco plants showed insecticidal activity against their lepidopteran pests, resulting in an iJAZ-based approach for generating alternative insecticidal proteins with distinctive mechanisms of action, thus holding immense potential for future crop engineering.

High-Grade Endometrial Cancer: Molecular Subtypes, Current Challenges, and Treatment Options.

Although many recent advancements have been made in women's health, perhaps one of the most neglected areas of research is the diagnosis and treatment of high-grade endometrial cancer (EnCa). The molecular classification of EnCa in concert with histology was a major step forward. The integration of profiling for mismatch repair deficiency and Human Epidermal Growth Factor 2 (HER2) overexpression, can further inform treatment options, especially for drug resistant recurrent disease. Recent early phase trials suggest that regardless of subtype, combination therapy with agents that have distinct mechanisms of action is a fruitful approach to the treatment of high-grade EnCa. Unfortunately, although the importance of diagnosis and treatment of high-grade EnCa is well recognized, it is understudied compared to other gynecologic and breast cancers. There remains a tremendous need to couple molecular profiling and biomarker development with promising treatment options to inform new treatment strategies with higher efficacy and safety for all who suffer from high-grade recurrent EnCa.

P162 Dimethyl fumarate modulates T cell metabolism and function in systemic lupus erythematosus patient samples

Abstract Background/Aims Activated CD4+T cells make a significant contribution to inflammation in systemic lupus erythematosus (SLE) through secretion of proinflammatory cytokines such as IFN-γ and TNF-α. CD4+T cells can also express activating NK receptors such as NKG2D that can engage with stress-induced ligands such as MICA, as noted in lupus nephritis, and mediate nonspecific tissue injury. We know that cellular metabolism regulates the activation of T cells. Evidence from patients with multiple sclerosis indicates that dimethyl fumarate (DMF), an electrophile, targets cellular metabolism to modulate CD4+T cell activation and function. Here, we investigated whether DMF modulates T cell metabolism and function in samples from patients with SLE in a series of in vitro experiments. Methods All experiments were performed using isolated T cells from freshly drawn whole blood samples from patients with SLE. T cells were isolated using negative selection using stem cell or Miltenyei magnetic bead separation kit. Isolated T cells were activated with anti-CD3 and IL-2 and incubated with either DMF at 25μM concentration or DMSO alone for three or seven days at 37 °C and 5% CO2 before harvesting. Results In Seahorse experiments, after three days of incubation, dimethyl fumarate (DMF) inhibited Figure A-i) the oxygen consumption rate (OCR) and A-ii) extra cellular acidification rate (ECAR) in isolated T cells when compared with samples incubated with vehicle, dimethyl sulfoxide (DMSO). Our results revealed that DMF significantly inhibited: 1) aerobic glycolysis and oxidative phosphorylation in activated T cells from patients with SLE (n = 4) (Figure A- i and ii) in vitro; 2) T cell activation and proliferation as assessed by a reduction in the frequency of CD69 (n = 4) and D) Ki67 (n = 2) positivity, respectively (Figure B-E); 3) Collectively, these results suggest that DMF inhibits T cell activation and proliferation in samples from patients with SLE. After 7 days of incubation, DMF significantly inhibited the expression of activating NK receptors CD158a and NKG2D on T cells whereas there was a trend toward enhancing the expression of inhibitory NK receptors NKG2A and CD158b (Figure F-I). After 7 days of incubation, DMF significantly reduced intracellular expression of IFN-γ, TNF-α, IL-17 and secretion of pro-inflammatory cytokines IFN-γ and TNF-α in supernatants (Figure J - N). Conclusion Our preliminary data indicated that, in SLE patient samples, DMF modulates metabolic programming of CD4+ T cells and inhibits glycolysis and oxidative phosphorylation of activated CD4+ T cells. In vitro, DMF inhibited: T cell activation; proliferation; the expression of activating NK receptors; and secretion of proinflammatory cytokines from T cells patients with SLE. Taken together with the existing safety data in humans, these data provide mechanistic rationale for investigating the potential of dimethyl fumarate, with a distinct mechanism of action, as a novel therapy for SLE. Disclosure L. Kell: None. K. Shah: None. S. Taylor: None. R. De Maeyer: None. D.A. Isenberg: None. D. Sen: None. M. Castelino: None. M. Leandro: None. A. Akbar: None. V. Reddy: Grants/research support; UCLH Biomedical research centre funded this work, Dr.Reddy's work was supported through MR/T024968/1 MRC-CARP Fellowship.

Bupleurum in Treatment of Depression Disorder: A Comprehensive Review.

The incidence of depression has been steadily rising in recent years, making it one of the most prevalent mental illnesses. As the pursuit of novel antidepressant drugs captivates the pharmaceutical field, the therapeutic efficacy of Traditional Chinese Medicine (TCM) has been widely explored. Chaihu (Bupleurum) has been traditionally used for liver conditions such as hepatitis, liver inflammation, liver fibrosis, and liver cancer. It is believed to have hepatoprotective effects, promoting liver cell regeneration and protecting against liver damage. In addition, Bupleurum has also been used as a Jie Yu (depression-relieving) medicine in China, Japan, Republic of Korea, and other Asian countries for centuries. This review article aims to summarize the research conducted on the antidepressant properties and mechanisms of Bupleurum, as well as discuss the potential of TCM formulas containing Bupleurum. This review highlights various antidepressant ingredients isolated from Bupleurum, including saikosaponin A, saikosaponin D, rutin, puerarin, and quercetin, each with distinct mechanisms of action. Additionally, Chinese herb prescriptions and extracts containing Bupleurum, such as Chaihu Shugansan, Xiaoyaosan, and Sinisan, are also included due to their demonstrated antidepressant effects. This review reveals that these Bupleurum compounds exhibit antidepressant effects through the regulation of neurotransmitter mechanisms (such as 5-HT and DA), the NMDA (N-methyl-D-aspartate) system, brain-derived neurotrophic factor (BDNF), and other intracellular signaling pathways. Collectively, this comprehensive review provides insights into the multiple applications of Bupleurum in the treatment of depression and highlights its potential as an alternative or complementary approach to traditional therapies. However, it is essential to consider the potential adverse effects and clinical restrictions of Bupleurum despite its promising potential. Further research is needed to elucidate its specific mechanisms of action and evaluate its effectiveness in human subjects.

Silver Organometallics that are Highly Potent Thioredoxin and Glutathione Reductase Inhibitors: Exploring the Correlations of Solution Chemistry with the Strong Antibacterial Effects.

The antibacterial activity of silver species is well-established; however, their mechanism of action has not been adequately explored. Furthermore, issues of low-molecular silver compounds with cytotoxicity, stability, and solubility hamper their progress to drug leads. We have investigated silver N-heterocyclic carbene (NHC) halido complexes [(NHC)AgX, X = Cl, Br, and I] as a promising new type of antibacterial silver organometallics. Spectroscopic studies and conductometry established a higher stability for the complexes with iodide ligands, and nephelometry indicated that the complexes could be administered in solutions with physiological chloride levels. The complexes showed a broad spectrum of strong activity against pathogenic Gram-negative bacteria. However, there was no significant activity against Gram-positive strains. Further studies clarified that tryptone and yeast extract, as components of the culture media, were responsible for this lack of activity. The reduction of biofilm formation and a strong inhibition of both glutathione and thioredoxin reductases with IC50 values in the nanomolar range were confirmed for selected compounds. In addition to their improved physicochemical properties, the compounds with iodide ligands did not display cytotoxic effects, unlike the other silver complexes. In summary, silver NHC complexes with iodide secondary ligands represent a useful scaffold for nontoxic silver organometallics with improved physicochemical properties and a distinct mechanism of action that is based on inhibition of thioredoxin and glutathione reductases.

Ligand-based virtual-screening identified a novel CFTR ligand which improves the defective cell surface expression of misfolded ABC transporters.

Cystic fibrosis (CF) is a monogenetic disease caused by the mutation of CFTR, a cAMP-regulated Cl- channel expressing at the apical plasma membrane (PM) of epithelia. ∆F508-CFTR, the most common mutant in CF, fails to reach the PM due to its misfolding and premature degradation at the endoplasmic reticulum (ER). Recently, CFTR modulators have been developed to correct CFTR abnormalities, with some being used as therapeutic agents for CF treatment. One notable example is Trikafta, a triple combination of CFTR modulators (TEZ/ELX/IVA), which significantly enhances the functionality of ΔF508-CFTR on the PM. However, there's room for improvement in its therapeutic effectiveness since TEZ/ELX/IVA doesn't fully stabilize ΔF508-CFTR on the PM. To discover new CFTR modulators, we conducted a virtual screening of approximately 4.3 million compounds based on the chemical structures of existing CFTR modulators. This effort led us to identify a novel CFTR ligand named FR3. Unlike clinically available CFTR modulators, FR3 appears to operate through a distinct mechanism of action. FR3 enhances the functional expression of ΔF508-CFTR on the apical PM in airway epithelial cell lines by stabilizing NBD1. Notably, FR3 counteracted the degradation of mature ΔF508-CFTR, which still occurs despite the presence of TEZ/ELX/IVA. Furthermore, FR3 corrected the defective PM expression of a misfolded ABCB1 mutant. Therefore, FR3 may be a potential lead compound for addressing diseases resulting from the misfolding of ABC transporters.

Synthesis, Plant Growth Regulatory Activity, and Transcriptome Analysis of Novel Opabactin Analogs.

Abscisic acid (ABA), a phytohormone, and its analogs have been found to enhance plant resistance to various biotic and abiotic stresses, particularly drought, by activating the ABA signaling pathway. This study used a combination of structure-directed design and molecular docking screening methods to synthesize a novel series of opabactin (OP) analogs. Among them, compounds 4a-4d and 5a showed comparable or superior activity to OP in bioassays, including seed germination and seedling growth inhibition in A. thaliana and rice, stomatal closure, and drought resistance in wheat and soybean. Further transcriptome analysis revealed distinct mechanisms of action between compound 4c and iso-PhABA in enhancing drought tolerance in A. thaliana. These findings highlight the application prospect of 4c and its analogs in agricultural cultivation, particularly in drought resistance. Additionally, they provide new insights into the mechanisms by which different ABA receptor agonists enhance drought resistance.

Microbiota dynamics preceding bariatric surgery as obesity treatment: a comprehensive review.

The review present data on the intricate relationship between bariatric surgery, gut microbiota, and metabolic health in obesity treatment. Bariatric surgery, is recognized as an effective intervention for managing morbid obesity, including various techniques with distinct mechanisms of action, efficacy, and safety profiles including Roux-en-Y Gastric Bypass (RYGB), Sleeve Gastrectomy (SG), Laparoscopic Adjustable Gastric Banding (LAGB), and Biliopancreatic Diversion (BPD). RYGB and SG are the most prevalent procedures globally, inducing gut microbiota changes that influence microbial diversity and abundance. Post-surgery, alterations in bacterial communities occur, such as the increased of Escherichia coli inversely correlated with fat mass and leptin levels. During digestion, microbiota produce physiologically active compounds like bile acids (Bas) and short-chain fatty acids (SCFAs). SCFAs, derived by microbial fermentation, influence appetite, energy metabolism, and obesity-related pathways. Bas, altered by surgery, modulate glucose metabolism and insulin sensitivity. Furthermore, SG and RYGB enhance incretin secretion, particularly glucagon-like peptide 1 (GLP-1). Therefore, understanding microbiota changes after bariatric surgery could be crucial for predicting metabolic outcomes and developing targeted interventions for obesity management.

Tricholoma matsutake polysaccharides suppress excessive melanogenesis via JNK-mediated pathway: Investigation in 8- methoxypsoralen induced B16–F10 melanoma cells and clinical study

Skin hyperpigmentation is a worldwide condition associated with augmented melanogenesis. However, conventional therapies often entail various adverse effects. Here, we explore the safety range and depigmentary effects of polysaccharides extract of Tricholoma matsutake (PETM) in an in vitro model and further evaluated its efficacy at the clinical level. An induced-melanogenesis model was established by treating B16–F10 melanoma cells with 8-methoxypsoralen (8-MOP). Effects of PETM on cell viability and melanin content were examined and compared to a commonly used depigmentary agent, α-arbutin. Expressions of key melanogenic factors and upstream signaling pathway were analysed by quantitative PCR and western blot. Moreover, a placebo-controlled clinical study involving Chinese females with skin hyperpigmentation was conducted to measure the efficacy of PETM on improving facial pigmented spots, melanin index, and individual typology angle (ITA°). Results demonstrated that PETM (up to 0.5 mg/mL) had little effect on the viability and motility of B16–F10 cells. Notably, it significantly suppressed the melanin content and expressions of key melanogenic factors induced by 8-MOP in B16–F10 melanoma cells. Western blotting results revealed that PETM inhibited melanogenesis by inactivating c-Jun N-terminal kinase (JNK), and this inhibitory role could be rescued by JNK agonist treatment. Clinical findings showed that PETM treatment resulted in a significant reduction of facial hyperpigmented spot, decreased melanin index, and improved ITA° value compared to the placebo-control group. In conclusion, these in vitro and clinical evidence demonstrated the safety and depigmentary efficacy of PETM, a novel polysaccharide agent. The distinct mechanism of action of PETM on melanogenic signaling pathway positions it as a promising agent for developing alternative therapies.

Abstract 1177: The chronology of immune-related adverse events (irAEs)-mechanistic implications

Abstract Immune Oncology (IO) is a novel component of the oncology armamentarium given its distinct mechanism of action, and by extension, unique mechanisms of toxicity (Tx). To recognize these unusual Txs, the term irAEs was popularized in clinical trials. Most organs have been involved by irAEs and autoimmunity has been implicated commonly by practicing oncologists. The onset of irAEs has not been studied well, however. We reasoned that autoimmune phenomena would be expected early after IO, since this is the timeframe within which T-cells expand to exert their effects on tumor and other ‘self’ tissues. It follows that if autoimmunity is the sole mechanism of irAEs, such toxicities should be reported early. Mechanism(s) of irARs may prove important for IO duration discussions. In some cases, tumor antigenic epitopes may mimic self-tissues, and in such cases irAEs develop early after initiation of IO. We hypothesized that irAEs have distinct chronology: earlier events representing autoimmunity (unavoidable); later events reflecting an intercurrent exposure to an antigen (e.g., virus) and therefore are avoidable by limiting duration of IO. Methods: We reviewed published IO monotherapy trials if individual patient data (swimmers’ plot) were reported. We derived the timing and frequency of Tx. We used therapy discontinuation without progressive disease as a surrogate for Tx if reported before the planned 24 months IO therapy.Results: Table depicts the data on included clinical trialsConclusion: The emergence of irAEs after IO extends over a protracted periods with 86% of events occurring beyond 4 months of IO. Though responses occasionally develop late after IO, for Tx consideration, T-cell expansion starts within days of IO initiation, and if autoimmunity is the mediator of Tx, irAEs would emerge only early. Our results suggest dual mechanisms and provide one more impetus to consider shortening IO duration. Tumor Author Discontinued IO (n) Months of IO Discontinuation 0-2 3-4 5-6 7-8 9-10 11-12 13-14 15-16 17-18 19-20 21-22 NSCLC Topalian 12 1 1 4 1 1 3 1 Dart 11 3 4 3 1 Warburton 56 2 2 7 8 7 22 1 3 1 2 1 Melanoma Topalian 13 4 1 2 1 2 2 1 Weber 2 1 1 Demetriou 66 8 4 6 5 6 10 6 10 6 5 RCC Topalian 3 1 2 Total 163 14 10 15 25 14 38 9 15 10 11 2 8% 6% 9% 15% 8% 23% 5% 9% 6% 7% 1% Citation Format: Farah Mazahreh, Haya Safar, Liyan Mazahreh, A. Mazin Safar. The chronology of immune-related adverse events (irAEs)-mechanistic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1177.

Abstract 1904: Preclinical development of MGC026, a glycan-linked, exatecan-based antibody-drug conjugate (ADC) targeting B7-H3 for solid cancer

Abstract Introduction: Antibody-drug conjugates (ADCs) have emerged as an important class of therapeutic agents for the treatment of cancer. A duocarmycin-based B7-H3-targeted DNA-alkylating ADC, vobramitamab duocarmazine (vobra duo), has shown encouraging clinical activity in the treatment of metastatic castration-resistant prostate cancer. Given the broad spectrum of tumor indications addressable by targeting B7-H3, we developed MGC026, an ADC incorporating a B7-H3-targeting antibody and a novel glycan-linked topoisomerase 1 inhibitor (TOP1i). With distinct mechanisms of action, vobra duo and MGC026 can address different cancers, tumor stages, or be used in combination with alternate agents to enhance their clinical utility. Methods: MGC026 is comprised of the cleavable linker-payload, bicyclononyne carbamoyl sulfamide Val-Ala-PABC exatecan (SYNtecan E™) site-specifically conjugated at asparagine 297 of the heavy chain through enzymatic glycan remodeling and metal-free click chemistry, using Synaffix’s GlycoConnect™ technology. In vivo efficacy studies were conducted in immunodeficient mice with human tumor cell-line or patient-derived xenografts to identify the spectrum of MGC026-sensitive tumors and the relationship between exposure and antitumor activity. A toxicology study was conducted in cynomolgus monkeys in which MGC026 was administered by 15-minute IV infusion once every three weeks. Pharmacokinetic (PK) analysis and detailed toxicology evaluation was performed. Results: MGC026 demonstrated specific, dose-dependent in vivo antitumor activity toward B7-H3-positive tumor xenografts representing lung, pancreatic, and prostate cancers, head and neck squamous cell carcinoma, and melanoma. Additionally, MGC026 demonstrated antitumor activity toward B7-H3-positive patient-derived xenograft models of lung and prostate cancer, with additional indications under investigation. MGC026, administered to cynomolgus monkeys at dose levels of 10, 30, and 50 mg/kg every 3 weeks for a total of 3 doses, exhibited approximate dose-proportional PK and high stability in circulation. MGC026 was well tolerated, with no lung toxicity observed, and the highest dose level tested (50 mg/kg) was declared as the highest non-severely toxic dose. Conclusions: MGC026 exhibited a favorable preclinical profile, with potent in vivo activity toward B7-H3-expressing tumor xenografts representing a range of cancer indications. MGC026 was tolerated in cynomolgus monkeys, a relevant toxicology model, at exposure levels exceeding those required for antitumor activity. These data support clinical development of MGC026 for the treatment of B7-H3-expressing solid cancers. Citation Format: Juniper A. Scribner, Jennifer G. Brown, Thomas Son, Linda Jin, Carroll McKenzie, Viktoriya Nam, Curtis Bush, Dienis Quinonez, James Tamura, Sergey Gorlatov, Hua Li, Shelley Butler, Ezio Bonvini, Deryk Loo. Preclinical development of MGC026, a glycan-linked, exatecan-based antibody-drug conjugate (ADC) targeting B7-H3 for solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1904.

Abstract 5705: Discovery of a selective slow-off CDK2 inhibitor NKT3447 with distinct features of suppressing pCDK2, downregulating cyclin E, and achieving prolonged pathway inhibition

Abstract CDK2 is a cell cycle kinase that plays a critical role in controlling the G1 to S-phase transition and its abnormal activation through cyclin E1(CCNE1) amplification has been indicated as the primary oncogenic driver in advanced cancers including ovarian, endometrial, and gastric cancers. In addition, cyclin E1 overexpression has emerged as a key resistance mechanism to CDK4/6 inhibitors in hormone receptor-positive breast cancer patients. Therefore, CDK2 represents a promising novel oncology target. However, development of a potent and selective CDK2 inhibitor has been challenging due to the high homology of CDK2 with other CDKs, particularly CDK1, which is essential in normal cell cycle progression. NKT3447 is a novel, orally bioavailable small molecule CDK2 inhibitor with slow-off kinetics and is highly selective against CDK1 and other CDKs. In addition, NKT3447 exhibits a distinct mechanism of action, including suppression of the Thr160 activating phosphorylation on CDK2 and downregulation of cyclin E1. In biochemical assays, NKT3447 drives a concentration dependent disruption of the CDK2/cyclin E1 and CDK2/cyclin A2 complexes, but not the CDK1/cyclin B1 complex. Consequently, NKT3447 potently inhibits the phosphorylation of Rb (pRb) and induces G1 cell cycle arrest in CCNE1 amplified OVCAR3 cells, while showing minimal or no effect on G2/M phase distribution in all the cell lines tested, including OVCAR3 and KYSE520 (CDK1-dependent) cells. Importantly, NKT3447 has a slow-off kinetics, as demonstrated by NanoBRET target engagement assay, which leads to sustained pRb inhibition after treatment withdrawal. In addition, NKT3447 treatment reduces cyclin E1 protein levels and suppresses phospho-CDK2 (Thr160), which further represses CDK2 activity and prolongs the inhibition of CDK2 signaling. NKT3447 also demonstrates a selective anti-proliferation effect in a panel of human cancer cell lines with elevated cyclin E1 expression and/or dependency on CDK2 or cyclin E1 (DepMap). In line with cellular studies, pharmacodynamic study of NKT3447 in mouse tumor models recapitulates a significant repression of pRb, pCDK2 and cyclin E1. Furthermore, NKT3447 treatment results in a dose-dependent tumor growth inhibition or tumor regression in CCNE1 amplified OVCAR3 and MKN1 tumor models. In addition, the combination of NKT3447 with carboplatin exhibits enhanced anticancer effects in OVCAR3 and MFE-280 models. These results demonstrate that NKT3447 is a potent, selective CDK2 inhibitor with distinct properties and mechanism of action, which holds great potential to effectively treat patients with aberrant CDK2/Cyclin E activation in a variety of cancer types. NKT3447 is currently being investigated in a Phase 1 clinical trial in patients with advanced solid tumors. Citation Format: Jianlin Geng, Ke Liu, Zhiyong Yu, Wenfeng Sun, Hairong Wei, Wenjun Li, Jing Lu, Juan Deng, Liqing Geng, Zhihong Liu, Zhenhai Gao, Yan Lou. Discovery of a selective slow-off CDK2 inhibitor NKT3447 with distinct features of suppressing pCDK2, downregulating cyclin E, and achieving prolonged pathway inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5705.

Practical management of disease-related manifestations and drug toxicities in patients with multiple myeloma.

Multiple myeloma (MM) is a very heterogeneous disease with multiple symptoms and clinical manifestations. MM affects mainly elderly patients and is difficult to manage in the presence of comorbidities, polypharmacy, frailty and adverse events of disease-targeted drugs. The rapid changes in MM treatment resulting from constant innovations in this area, together with the introduction of numerous new drugs with distinct mechanisms of action and toxicity profiles, have led to an increased complexity in the therapeutic decision-making and patient management processes. The prolonged exposure to novel agents, sometimes in combination with conventional therapies, makes this management even more challenging. A careful balance between treatment efficacy and its tolerability should be considered for every patient. During treatment, a close monitoring of comorbidities, disease-related manifestations and treatment side effects is recommended, as well as a proactive approach, with reinforcement of information and patient awareness for the early recognition of adverse events, allowing prompt therapeutic adjustments. In this review, we discuss various issues that must be considered in the treatment of MM patients, while giving practical guidance for monitoring, prevention and management of myeloma-related manifestations and treatment-related toxicities.

Abstract 5293: Preclinical development of NI-3201, a PD-L1xCD28 bispecific antibody mediating CD28 costimulation upon PD-L1 blockade

Abstract NI-3201 is a PD-L1xCD28 bispecific antibody generated on the κλ body platform that blocks the PD-L1/PD-1 immune checkpoint pathway and conditionally provides T cell activation “signal 2” when engaging PD-L1+ tumor or immune cells (e.g., antigen-presenting cells). By combining two distinct mechanisms of action into a single molecule, NI-3201 overcomes two major immune suppression mechanisms commonly observed in a variety of solid tumors, namely: [1] suppression of T cell response (induced by PD-L1+ cells engaging PD-1 on T cells) and [2] restricted/limited T cell activation (due to the lack of costimulatory signal associated to the scarcity of CD28 ligands in the TME). Importantly, NI-3201 was designed to require primary T cell stimulation (“signal 1”) to afford its activity: in the absence of TCR engagement, NI-3201 is unable to activate T cells, thus preventing unintended systemic inflammation. The single agent pharmacological activity of NI-3201 was assessed in vitro through a Cytomegalovirus (CMV) recall assay in which CMV+ PBMCs were cocultured with PD-L1+ cancer cell lines ectopically loaded with CMV-specific MHC-I peptides, thus providing “signal 1”. NI-3201 induced the activation and proliferation of CMV-specific T cells which resulted in killing of the target tumor cells. In vivo, the single agent activity of NI-3201 was shown in immunocompetent huCD28-transgenic mice engrafted with huPD-L1-expressing murine colon adenocarcinoma MC38 cells, a model in which NI-3201 induced durable anti-tumor immunological memory response. In humanized mouse models where T cell engagers (TCEs) were ineffective, NI-3201 was able to synergize with TCEs to control tumor growth, even inducing tumor regression in one model. The pharmacokinetics (PK) and tolerability of NI-3201 were investigated in non-human primates (NHP) after single and repeated-dosing. NI-3201 demonstrated favorable PK with close to dose-proportional concentrations being achieved. Upon repeated NI-3201 administration, no hypercytokinemia was observed; only a mild and transient IL-6 release and associated increase in C-reactive protein (CRP) levels were seen, with no clinical signs reported. The favorable profile seen in NHP was supported by data generated in vitro further de-risking the cytokine release syndrome (CRS) potential. Quantitative systems pharmacology (QSP) modelling integrating both in vitro and NHP data predicted a drug concentration required for optimal NI-3201 activity in the TME, and preliminary data suggests optimal patient activity at Q2W-Q3W dosing schedule. The anti-tumor activity as a single agent or as universal combination partner for TCEs, shown in vitro and in vivo, together with the favorable safety profile of NI-3201, support its clinical development planned to start in Q1 2025. Citation Format: Sara Majocchi, Nadia Anceriz, Alizée Viandier, Adeline Lesnier, Laura Cons, Lise Nouveau, Emily A. Pace, Bjorn L. Millard, Bruno Daubeuf, Valéry Moine, Susana Salgado-Pires, José Saro, Limin Shang, Krzysztof Masternak, Walter G. Ferlin. Preclinical development of NI-3201, a PD-L1xCD28 bispecific antibody mediating CD28 costimulation upon PD-L1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5293.

Catalysts of Healing: A Symphony of Synthesis and Clinical Artistry in Small-Molecule Agents for Breast Cancer Alleviation.

Breast cancer, characterized by its molecular intricacy, has witnessed a surge in targeted therapeutics owing to the rise of small-molecule drugs. These entities, derived from cutting-edge synthetic routes, often encompassing multistage reactions and chiral synthesis, target a spectrum of oncogenic pathways. Their mechanisms of action range from modulating hormone receptor signaling and inhibiting kinase activity, to impeding DNA damage repair mechanisms. Clinical applications of these drugs have resulted in enhanced patient survival rates, reduction in disease recurrence, and improved overall therapeutic indices. Notably, certain molecules have showcased efficacy in drug-resistant breast cancer phenotypes, highlighting their potential in addressing treatment challenges. The evolution and approval of small-molecule drugs have ushered in a new era for breast cancer therapeutics. Their tailored synthetic pathways and defined mechanisms of action have augmented the precision and efficacy of treatment regimens, paving the way for improved patient outcomes in the face of this pervasive malignancy. The present review embarks on a detailed exploration of small-molecule drugs that have secured regulatory approval for breast cancer treatment, emphasizing their clinical applications, synthetic pathways, and distinct mechanisms of action.

Repurposing disulfiram with CuET nanocrystals: Enhancing anti-pyroptotic effect through NLRP3 inflammasome inhibition for treating inflammatory bowel diseases

Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing drugs. Recently, disulfiram (DSF), a drug primarily used for alcohol addiction treatment, has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis, a form of programmed cell death. The therapeutic activity of DSF can be further enhanced by the presence of Cu2+, although the underlying mechanism of this enhancement remains unclear. In this study, we investigated the mechanistic basis of Cu2+-induced enhancement and discovered that it is attributed to the formation of a novel copper ethylthiocarbamate (CuET) complex. CuET exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of action. However, despite its potent activity, CuET suffered from poor solubility and limited permeability, as revealed by our druggability studies. To overcome these intrinsic limitations, we developed a scalable method to prepare CuET nanocrystals (CuET NCs) using a metal coordination-driven self-assembly approach. Pharmacokinetic studies demonstrated that CuET NCs exhibited a 6-fold improvement in bioavailability. Notably, CuET NCs exhibited high biodistribution in the intestine, suggesting their potential application for the treatment of inflammatory bowel diseases (IBDs). To evaluate their therapeutic efficacy in vivo, we employed a murine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis symptoms. Our findings highlight the discovery of CuET as a potent anti-pyroptotic agent, and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.