Favorable Pharmacokinetic Profile Research Articles

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

Suprachoroidal Drug Delivery for Macular Edema Associated With Noninfectious Uveitis.

Purpose: To evaluate clinical trials in the literature that focus on suprachoroidal drug delivery for the treatment of noninfectious uveitis and other posterior segment diseases. Methods: A synthesis of the literature was performed. Results: In 2021, suprachoroidal space triamcinolone acetonide, a corticosteroid delivery system used for the treatment of uveitic macular edema (ME), was approved by the US Food and Drug Administration. The drug-delivery system targets the suprachoroidal space using a microneedle-based device and has a favorable pharmacokinetic profile. Suprachoroidally administered investigational therapies have also been assessed in clinical trials for other posterior segment diseases, including diabetic ME, retinal vein occlusion, age-related macular degeneration, and choroidal melanoma. Conclusions: The safety and efficacy of suprachoroidal corticosteroid injections to treat uveitic ME have been shown in recent phase III clinical trials. Multiple programs are also investigating this modality of drug delivery for use in many other retinal and choroidal pathologies.

Design, Synthesis, Formulation, and Bioevaluation of Trisubstituted Triazines as Highly Selective mTOR Inhibitors for the Treatment of Human Breast Cancer.

The aberrant activation of the PI3K/mTOR signaling pathway is implicated in various human cancers. Thus, the development of inhibitors targeting mTOR has attracted considerable attention. In this study, we used a structure-based drug design strategy to discover a highly potent and kinase-selective mTOR inhibitor 24 (PT-88), which demonstrated an mTOR inhibitory IC50 value of 1.2 nM without obvious inhibition against another 195 kinases from the kinase profiling screening. PT-88 displayed selective inhibition against MCF-7 cells (IC50: 0.74 μM) with high biosafety against normal cells, in which autophagy induced by mTOR inhibition was implicated. After successful encapsulation in a lipodisc formulation, PT-88 demonstrated favorable pharmacokinetic and biosafety profiles and exerted a large antitumor effect in an MCF-7 subcutaneous bearing nude mice model. Our study shows the discovery of a highly selective mTOR inhibitor using a structure-based drug discovery strategy and provides a promising antitumor candidate for future study and development.

Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers.

Male HVs were randomized to receive oral BI 1358894 (n = 18) or placebo (n = 6) after a high-fat, high-calorie meal within three dose groups (50mg, 100mg, 200mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894. Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4-6h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group. BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs. ClinicalTrials.gov (NCT03875001; 08-Mar-2019).

The Class I Histone Deacetylase Inhibitor as a Potent Therapeutic Target for Treating Glioblastoma and Mocetinostat as a Novel Inhibitor in the Induction Death of Cancer Cells

Epigenetic abnormality is one of the hallmarks of glioblastoma cancer cells. Histone deacetylase (HDAC) modification has a crucial role in epigenetic abnormality, which results in the initiation and progression of glioblastoma cancer cells. The selective HDAC inhibitors are well-known epigenetic regulators and promising anti-cancer agents that target specific HDAC enzymes and inhibit the proliferation of many cancer cells. Selective HDAC inhibitors isoform provides a high efficacy as chemotherapy in inhibiting cancer confirmation compared to non-selective HDAC inhibitors. Additionally, selective HDAC inhibitors suppress Class -I HDAC1, HDAC2, HDAC3, and HDAC11. HDAC class I inhibitors induce apoptosis, differentiation, autophagic death cells, and reactive oxygen species (ROS)- induced cell death, inhibit cell migration, invasion, and angiogenesis in cancer cells, while the normal cells showed more resistance to HDAC class I inhibitors. Mocetinostat (MGCD0103), a benzamide histone deacetylase, is a potent anti-cancer therapy for the treatment of several cancer cell lines and induction of autophagy. It has been approved by The Food and Drug Administration (FDA) for the treatment of Hodgkin lymphoma (HL) cell lines. MGCD0103 is a synthesized and selective HDAC inhibitor that has vigorous inhibitory activity against Class-I and IV HDAC. MGCD0103 is well tolerated and has favorable pharmacokinetic properties, pharmacodynamic profile, and fast absorption within 1 hour after oral administration, long elimination half-life, and sustained HDAC inhibition. Therefore, MGCD0103 is expected to be a promising anti-cancer drug for treating several types of human cancer cells. Keywords: MGCD0103; Apoptosis; Differentiation; Gliblastoma; HDAC; inhibitors.

Discovery of Sovleplenib, a Selective Inhibitor of Syk in Clinical Development for Autoimmune Diseases and Cancers.

Herein we describe the medicinal chemistry efforts that led to the discovery of the clinical-staged Syk inhibitor sovleplenib (41) via a structure-activity relationship investigation and pharmacokinetics (PK) optimization of a pyrido[3,4-b]pyrazine scaffold. Sovleplenib is a potent and selective Syk inhibitor with favorable preclinical PK profiles and robust anti-inflammation efficacy in a preclinical collagen-induced arthritis model. Sovleplenib is now being developed for treating autoimmune diseases such as immune thrombocytopenic purpura and warm antibody hemolytic anemia as well as hematological malignancies.

In silico rationalization of piperidin-4-one analogs as anaplastic lymphoma kinase inhibitors: Integration of density functional theory, topological descriptor, molecular docking and pharmacological feature profiling

Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. Hence, developing new ALK inhibitors which can overcome resistance is essential. Here, we designed a novel ALK inhibitor Piperidin-4-One based on the structure of the second-generation ALK inhibitor ceritinib. The target compound 1-(cyclopropanecarbonyl)-2,6-bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-methylpiperidin-4-one (CDMP) was computed using density functional theory (DFT) method. The stability and charge delocalization of the molecule was also studied by natural bond orbital (NBO) analysis. The HOMO-LUMO energies describe the charge transfer takes place within the molecule. Molecular electrostatic potential has been analyzed. The reported molecule used as a potential NLO material since it has high µβ0 value. Additionally, statistical analyses were conducted to clarify the connections between ADMET properties of CDMP and molecular descriptors based on degree, neighborhood degree, degree entropy and neighborhood degree entropy. This thorough examination seeks to uncover the complex interactions between Density Functional Theory and molecular descriptors, offering valuable insights into the relationships among CDMP drug properties. The binding mode mechanism of the title compound was investigated through molecular docking studies, focusing on cancer-related proteins such as 4TT7, 5FTO and 3AOX. Furthermore, an assessment of Drug-likeness and ADMET properties revealed favorable pharmacokinetic profiles for the compound, with no indications of toxicity observed.

Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease.

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

Abstract LB298: Simultaneous reprogramming of glioblastoma tumor cells and tumor-associated macrophages by tumor-suppressive microRNA

Abstract Therapeutic outcomes in glioblastoma (GBM) patients remain dismal due to its resistance to conventional therapies. Tumor-supportive tumor microenvironment (TME) that is educated by tumor cells through immune editing is not properly primed for the treatment. Targeted reprogramming of both tumor cells and tumor-associated macrophages (TAMs) is expected to prime the tumor cells and the immunosuppressive TME. Tumor suppressive microRNAs (miRNAs) have been proposed as the most suitable therapeutic target to perform the tumor reprogramming role. We recently identified miR-138 as a putative tumor suppressive miRNA that can reprogram GBM tumor. However, achieving the simultaneous targeted reprogramming of two distinct cell types is a complex challenge, demanding a selective delivery system to minimize adverse side effects. Previously, we demonstrated that extracellular vesicles (EVs) can serve as carriers for the selective delivery of small noncoding therapeutic RNAs into cancer cells through the EV surface labeling with cancer-targeting ligands. Here, we report that the trypsin digestion of EV surface can enhance their surface labeling efficiency with cancer targeting ligands, such as folate, with favorable bio-distribution and pharmacokinetic profiles in GBM mice model. The folate-labeled trypsinized EVs demonstrated a potential to selectively target folate receptor (FR) positive GBM cells and TAMs both in vitro and in vivo. The selective targeting of folate-labeled trypsinized EVs led to the targeted delivery of miR-138 into both GBM tumor cells and TAMs, achieving anti-tumor efficacy. Mechanism of action studies revealed that the ectopically delivered miR-138 inhibits its previously identified known target genes to reprogram tumor cell proliferation and macrophage polarization. To our knowledge, this is the first preclinical study attempting to simultaneously modulate tumor cells and innate immunity by delivering tumor suppressive miR-138 using the trypsinized EV-based RNA delivery system for the GBM treatment. Our study results can be rapidly translated into human clinical trials in combination with current immunotherapies. Citation Format: Grace Nguyen, MinHye Noh, Yulin Dai, Zhongming Zhao, Ji Young Yoo, Tae Jin Lee. Simultaneous reprogramming of glioblastoma tumor cells and tumor-associated macrophages by tumor-suppressive microRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB298.

Abstract LB269: XZP-6924: A potent and highly selective USP1 inhibitor with the potential to improve efficacy and overcome resistance to PARP inhibitors

Abstract Genomic instability exists in most cancer cells, making them more dependent on certain DDR repair pathways. Existing research shows that inhibition of the DNA damage response (DDR) pathway stresses cell replication and survival. Drugs targeting the DDR pathway are effective in the treatment of many types of cancers, such as the approved Poly (ADP-ribose) polymerase (PARP) inhibitors that cause synthetic lethality to the cancers harboring BRCA1/2 mutations and other homologous repair deficiencies (HRD). Although PARP inhibitors have good clinical performance, not all patients respond to PARP inhibitor treatments. In addition, the effectiveness of PARP inhibitors in clinics is also limited by the rise of treatment-related drug resistance. Ubiquitin-specific protease 1 (USP1) is involved in DNA damage repair processes, including translesion synthesis and Fanconi anemia pathways. It has been well documented that USP1 deficiency leads to replication fork instability and synthetic lethality to HRD. Combination of USP1 inhibitors with PARP inhibitors synergistically targets BRCA1/2 mutant cancers, thereby enhancing the antitumor effect and reducing drug resistance to PARP inhibitors.We have developed a potent and highly selective USP1 inhibitor, XZP-6924. The selective inhibition of USP1 by XZP-6924 results in the accumulation of mono-ubiquitinated USP1 substrates, for example, proliferating nuclear antigen (PCNA), leading to DNA double-strand breaks (DSBs) and widespread DNA damage accumulation that contributes to cell death. In vitro data reveal that XZP-6924, when combined with Olaparib (PARPi), displays significantly enhanced activities in multiple Olaparib-resistant HRD tumor cells. In CDX and PDX mouse tumor models, XZP-6924 at low doses demonstrates synergy and superior efficacy with sustained tumor regression when combined with a PARP inhibitor (Olaparib). Furthermore, XZP-6924 possesses favorable ADME properties and pharmacokinetic profiles in preclinical animal species. Preliminary toxicology study data indicate that XZP-6924 is well tolerated with a favorable safety margin.In conclusion, XZP-6924 is a potent and highly selective USP1 inhibitor that has the potential for the combination therapy with PARP inhibitors to increase efficacy and overcome some primary and acquired resistance to PARP inhibitors. Current data strongly support further development of XZP-6924. The IND submission is expected in the second half of 2024. Citation Format: Zhihui Kan, Shujin Bai, Kelin Ma, Bo Chen, Benke Jiang, Feng Wang, Xifeng Ma, Dapeng Zhou, Chunmin Shi, Yanfang Nie, Yunling Wang, Ruxiao Liu, Jun Sun, Huimin Zhou, Mei Xu, Jiakui Li, Bin Liu. XZP-6924: A potent and highly selective USP1 inhibitor with the potential to improve efficacy and overcome resistance to PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB269.

Abstract CT183: Initial results from a phase 1a/1b study of STK-012, a first-in-class α/β IL-2 receptor biased partial agonist in advanced solid tumors (NCT05098132)

Abstract Background: STK-012 is a first-in-class α/β-IL-2R biased partial agonist designed to drive antitumor activity by selectively stimulating CD25+ antigen activated T cells, while avoiding hallmark IL-2 toxicities by sparing pleotropic activation of lymphocytes including NK cells. Methods: STK-012-101 is a Phase 1a/b study of STK-012 administered subcutaneously in subjects with advanced, relapsed/refractory (r/r) solid tumors. During Phase 1a, subjects are enrolled in a 3+3 dose escalation to STK-012 as monotherapy (QW or Q3W) or STK-012 + pembrolizumab (Q3W) followed by Phase 1b expansions. Results: Phase 1a and preliminary Phase 1b data are being presented for STK-012 monotherapy. As of Oct 23rd, 2023, 45 subjects were treated at 7 dose levels (DL) across 2 schedules (QW at 0.375 mg and 0.75mg; Q3W at 0.75mg-3mg). The most common tumors were NSCLC (35.6%) and RCC (20%). The most common treatment related AEs (TRAEs) were maculo-papular rash (38%), injection site reactions (28.9%), fatigue (28.9%), and nausea (24.4%). Grade 3 TRAEs occurred in 12 subjects (26.6%) and included maculo-papular rash (4), vomiting (2), nausea (1), diarrhea (1), enterocolitis (1), arthralgia (1), urticaria (1), periorbital edema (1), blood creatinine increase (1) and leukocytosis (1). One subject had a Grade 4 TRAE of anaphylaxis in Cycle 9 after the data extract date. TRAEs were reversible, and no subjects had Grade 5 TRAEs. No subjects had capillary leak syndrome and <5% experienced other IL-2 hallmark TRAEs (hypotension [4.4%], AST/ALT increase [0%], pyrexia [4.4%], peripheral edema [4.4%]). No DLTs were observed. The maximum administered dose of STK-012 was 3mg Q3W. A DL of 2.25mg Q3W was advanced into Phase 1b based on safety, pharmacokinetic (PK) and pharmacodynamic (PD) data. Peripheral PD data showed STAT5 phosphorylation in CD25+ T cells and a dose dependent increase in activated T cells (Ki-67+CD38+CD8+) and serum IFNγ. Expansion of NK cells and Tregs was limited. STK-012 has a half-life of 4 days. Of 38 efficacy evaluable subjects, 3 had a partial response (PR) and 17 had stable disease as best overall response by RECIST V1.1. The PRs included 2 confirmed (anti-PD-1 r/r NSCLC and RCC) and 1 unconfirmed (anti-PD-1 r/r SCCHN) with the RCC subject in response for over 9 months with treatment ongoing. After the data extract date, a fourth subject achieved a PR (confirmed) with 80% reduction in target lesions (anti-PD-1/CTLA-4 and TKI r/r RCC) with treatment ongoing. Monotherapy Phase 1b dose expansions in r/r NSCLC and r/r RCC are ongoing. Conclusions: In our ongoing Phase 1a/b trial, STK-012 demonstrated a favorable safety, PK, and PD profile which is distinct from that of aldesleukin and non-α IL-2 analogues. Peripheral PD and PK data support selectivity for IL-2R α/β. Preliminary monotherapy efficacy in subjects who are r/r to prior immunotherapy warrants further development. Citation Format: Benjamin Izar, Dmitriy Zamarin, David R. Spigel, Christopher J. Hoimes, David F. McDermott, Kartik Sehgal, Yana G. Najjar, Adam J. Schoenfeld, Edward B. Garon, Ryan J. Sullivan, Brian S. Henick, Ticiana A. Leal, Michael E. Hurwitz, Rana R. McKay, Natalie Busby, Anita Mehta-Damani, Alex Azrilevich, Tony Tran, Naiyer Rizvi, Martin Oft, Alexander I. Spira. Initial results from a phase 1a/1b study of STK-012, a first-in-class α/β IL-2 receptor biased partial agonist in advanced solid tumors (NCT05098132) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT183.

Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening.

DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.

VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response

VISTA, an inhibitory myeloid-T-cell checkpoint, holds promise as a target for cancer immunotherapy. However, its effective targeting has been impeded by issues such as rapid clearance and cytokine release syndrome observed with previous VISTA antibodies. Here we demonstrate that SNS-101, a newly developed pH-selective VISTA antibody, addresses these challenges. Structural and biochemical analyses confirmed the pH-selectivity and unique epitope targeted by SNS-101. These properties confer favorable pharmacokinetic and safety profiles on SNS-101. In syngeneic tumor models utilizing human VISTA knock-in mice, SNS-101 shows in vivo efficacy when combined with a PD-1 inhibitor, modulates cytokine and chemokine signaling, and alters the tumor microenvironment. In summary, SNS-101, currently in Phase I clinical trials, emerges as a promising therapeutic biologic for a wide range of patients whose cancer is refractory to current immunotherapy regimens.

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

Purpose5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU.Patients and methodsNUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity.ResultsFifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival.ConclusionNUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies.Trial registrationClinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240.

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer

Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.

Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer.

CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and are promising cancer therapeutic targets. Herein, we report the discovery of highly potent, selective, and orally bioavailable CBP/p300 degraders using the PROTAC technology with CBPD-409 being the most promising compound. CBPD-409 induces robust CBP/p300 degradation with DC50 0.2-0.4 nM and displays strong antiproliferative effects with IC50 1.2-2.0 nM in the VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. It has a favorable pharmacokinetic profile and achieves 50% of oral bioavailability in mice. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue. CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers.

Discovery of TK-642 as a highly potent, selective, orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5%; t1/2 = 2.47 h). Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the “tunnel” allosteric site of SHP2. TK-642 could effectively suppress cell proliferation (KYSE-520 cells IC50 = 5.73 μmol/L) and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways. Additionally, oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model, with a T/C value of 83.69%. Collectively, TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

A Review of FDA-Approved Anti-HIV-1 Drugs, Anti-Gag Compounds, and Potential Strategies for HIV-1 Eradication.

Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, the multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for the discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body's health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from patients' bodies. A potential strategy called "lock-in and apoptosis" targets the budding phase of the life cycle of the virus and leads to susceptibility to apoptosis of HIV-1 infected cells for the elimination of HIV-1 reservoirs and, ultimately, for complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA)-approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.

Abstract 7279: Discovery of SHR1127, an orally bioavailable, highly potent and selective KRAS G12D inhibitor

Abstract Mutant KRAS is the most frequent oncogenic driver in nearly 23% of human cancers. As the most common KRAS alteration, KRAS G12D mutation occurs in approximately 35%, 13%, and 4% of pancreatic, colorectal, and non-small cell lung cancers, respectively. It was worth noting that the clinical PoC of KRAS G12D inhibitor has been preliminarily validated by intravenous administration of HRS-4642 weekly. However, there still represents an extraordinary unmet clinical need requiring an oral KRAS G12D inhibitor featuring higher potency and favorable pharmacokinetic profiles. We disclose herein the development of an orally bioavailable, highly potent and selective KRAS G12D inhibitor, SHR1127.SHR1127 demonstrated picomolar binding affinity, with a KD value of 0.06 nM in a SPR binding assay with GDP-loaded KRAS G12D protein. SHR1127 significantly inhibited ERK phosphorylation with IC50s of 0.05 nM and 0.19 nM in GP2d and AGS cell lines, respectively. More importantly, 3D viability assay showed that SHR1127 displayed extremely high anti-proliferative activity against GP2d, AGS and AsPC-1 cell lines with the IC50s of 0.05, 0.83 and 0.92 nM, respectively. The selectivity over KRAS WT PC9 cells, KRAS G12C and G12V mutant cell lines was more than 500-fold. Additionally, SHR1127 displayed excellent human hepatocyte stability (T1/2 &amp;gt; 1000 min) and desirable physicochemical properties. Moreover, SHR1127 exhibited favorable pharmacokinetic profiles with dose-dependent exposure and acceptable oral bioavailability. In the GP2d xenograft model, SHR1127 showed a robust anti-tumor activity in a dose-dependent manner, leading to tumor regression (TGI = 125%) as low as 5 mg/kg (p.o. dosage, bid), without body-weight loss during 21 days of treatment. Furthermore, SHR1127 demonstrated no off-target activities at 1000 nM in 97 kinase panel and 78 safety panel screening. SHR1127 showed good safety window in the 14-day toxicology study in rat and dog. In summary, SHR1127 has been successfully developed as an orally bioavailable KRAS G12D inhibitor, exhibiting excellent cellular activities with good selectivity over KRAS WT. More importantly, SHR1127 showed favorable pharmacokinetic profiles across species, and robust tumor regression in a GP2d xenograft model at the dose of 5 mg/kg. In addition, SHR1127 demonstrated no off-target toxicity and good safety window. An IND submission for SHR1127 is planned in the first half of 2024. Citation Format: Xin Li, Feng Shen, Limin Zhang, Wei Wang, Luyao Kong, Yong Bao, Yuchang Mao, Zaiyong Wang, Sophie Lin, Zhe Zhang, Jun Feng, Min Hu, Feng He. Discovery of SHR1127, an orally bioavailable, highly potent and selective KRAS G12D inhibitor [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 7279.

Abstract 1884: DXC006, Anti-CD56-CPT113 ADC displays favorable anti-tumor efficacy, pharmacokinetic and safety profiles in preclinical studies

Abstract CD56, also known as neural cell adhesion molecule 1 (NCAM1), is a type I plasma membrane glycoprotein involved in cell-cell and cell-matrix adhesion. It is overexpressed in almost all neuroblastomas, 95% of small cell lung cancers and 78% of multiple myeloma patients[1], whereas CD56 is less frequently or less abundantly expressed in normal tissues, making it a potential target for tumor therapy. So far, no CD56-targeting ADCs have entered late-stage clinical trials.DXC006 is an antibody-drug conjugate of a humanized anti-CD56 antibody (DXA006) linked to the topoisomerase I inhibitor CPT113 through a cleavable peptidyl linker and CROSSCONJU™ technology. The pharmacologic activity and mechanism of action of DXC006 were investigated in several human cancer cell lines and xenograft mouse models. Pharmacokinetic and safety profiles were also assessed in rats and cynomolgus monkeys.DXC006 binds specifically to CD56 and internalizes into tumor cells, after intracellular trafficking to lysosome and CPT113 releasing, induces DNA damage. In vitro cell based assays showed that DXC006 remarkably inhibited the cell growth of CD56-positive cell lines of IMR-32 (neuroblastoma), NCI-H526 (small cell lung cancer), and NCI-H929 (multiple myeloma), with IC50 of 0.0046~0.061 nmol/L. Although DXC006 also binds to CD56 expressed NK cells, we found that the inhibition of DXC006 to human NK cells was much less effective, with IC50 higher than 675 nmol/L, which is ten thousand-folds less potent than that of targeted abnormal cells. In vivo, DXC006 demonstrated good durable antitumor activities in three CD56-positive xenograft models of IMR-32, NCI-H526 and NCI-H929 cell lines, with a single dose of 2 mg/Kg, 3 mg/Kg, and 5 mg/Kg, respectively. No animal death or moribund outcome was observed in two months during preclinical safety studies in 150 mg/Kg Q2W dosed rats. For cynomolgus monkeys, the highest non-severely toxic dose (HNSTD) of DXC006 was 20 mg/Kg, in Q2W, four times of administration. PK profiles of both DXC006 the naked antibody DXA006 were comparable in both rats and monkeys. In summary, DXC006 demonstrated strong antitumor activity in various types of cancer cells both in vitro and in vivo, and good pharmacokinetic and safety profiles in rat and monkeys, a potential to be explored in clinical applications. [1] Yang Feng, Yanping Wang, Zhongyu Zhu, et al. Differential killing of CD56-expressing cells by drug-conjugated human antibodies targeting membrane-distal and membrane-proximal nonoverlapping epitopes. mAbs 2016; 799-810. Citation Format: Xiangfei Kong, Huihui Guo, Yong Du, Zhicang Ye, Yongxiang Chen, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Mengmeng Liu, Binbin Chen, Meng Dai, Juan Wang, Fang Du, Miaomiao Chen, Qingliang Yang, Robert Y. Zhao. DXC006, Anti-CD56-CPT113 ADC displays favorable anti-tumor efficacy, pharmacokinetic and safety profiles in preclinical studies [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 1884.