Active Antitumor Agent Research Articles

Abstract 2026: Single-cell RNA-sequencing analysis of tumor endothelial cells reveals suppression of specific endothelial subtypes by the combination treatment of Wnt/β-catenin signaling modulator E7386 plus lenvatinib

Abstract Background: Aberrant activation of Wnt/β-catenin signaling plays an important role in both carcinogenesis and modulation of the tumor microenvironment. E7386, a novel orally active antitumor agent, inhibits the interaction between β-catenin and CREB-binding protein (CBP) and thereby modulates Wnt/β-catenin signaling. We previously reported that E7386 in combination with lenvatinib (LEN), a multiple receptor tyrosine kinase inhibitor mainly targeting VEGFRs and FGFRs, showed a greater antitumor activity and reduction of tumor microvessels than each treatment alone in preclinical tumor models. Multiple clinical studies are in progress including the combination of E7386 plus LEN (NCT04008797). Here, we further tried to elucidate the mechanism underlying the antitumor and antiangiogenic effect of the combination of E7386 plus LEN by using single-cell RNA sequencing (scRNA-seq) of tumor endothelial cells (ECs). Methods: Mice bearing subcutaneous RAG (mouse renal cell carcinoma cell line) tumors were treated with E7386 at 25 mg/kg and/or with LEN at 10 mg/kg by daily oral gavage for 8 days. Tumor ECs (CD31+/CD45−) were isolated by magnetic cell separation and flow cytometry and were subjected to scRNA-seq using 10x Genomics pipeline. Bioinformatics data analysis was conducted by Clarivate Analytics. After quality control and filtering, ECs were gated by their expression of pan-EC markers and were further classified into 9 subtypes (tip, capillary, arterial, venous, proliferating, immature, interferon, activated artery, and lymphatic) according to previously reported markers for each subtype. Results: Among classified subtypes, proliferating and immature subtypes showed clear reduction in the percentage of total ECs with combination of E7386 plus LEN versus LEN monotherapy. In both proliferating and immature subtypes, a subset of Wnt/β-catenin downstream genes showed increased expression with LEN monotreatment. Conversely, these Wnt/β-catenin downstream genes were downregulated with the combination of E7386 plus LEN, suggesting that Wnt/β-catenin signaling may be associated with a drug resistance mechanism against LEN in these subtypes. Pathway analysis indicated that genes involved in cell proliferation and survival were downregulated by the E7386 plus LEN combination versus LEN monotreatment in both proliferating and immature subtypes. Conclusion: Taken together, these results suggest a role for E7386 in suppressing the activation of Wnt/β-catenin signaling induced by LEN monotreatment in specific EC subtypes; this activity leads to enhanced antiangiogenic and antitumor activity with E7386 plus LEN combination therapy in a preclinical tumor model. Citation Format: Masahiko Kume, Ryoga Ishida, Yoichi Ozawa, Jialing Shen, Hiroto Konishi, Megumi Kuronishi, Takayuki Kimura, Yusuke Adachi, Yu Kato. Single-cell RNA-sequencing analysis of tumor endothelial cells reveals suppression of specific endothelial subtypes by the combination treatment of Wnt/β-catenin signaling modulator E7386 plus lenvatinib [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 2026.

Nanodiamonds-in-oil emulsions elicit potent immune responses for effective vaccination and therapeutics.

Background: The use of nanodiamonds (NDs) and fluorescent nanodiamonds (FNDs) as nonallergenic biocompatible additives in incomplete Freund's adjuvant (IFA) to elicit immune responses in vivo was investigated. Methods: C57BL/6 mice were immunized with chicken egg ovalbumin (OVA) in IFA and alsoOVA-conjugated NDs (or OVA-conjugated FNDs) in IFA to produce antibodies. OVA-expressing E.G7 lymphoma cells and OVA-negative EL4 cells were inoculated in mice to induce tumor formation. Results: The new formulation significantly enhanced immune responses and thus disease resistance. It exhibited specific therapeutic activities, effectively inhibiting the growth of E.G7 tumor cells in mice over 35days. Conclusion: The high biocompatibility and multiple functionalities of NDs/FNDs render them applicable as active and trackable vaccine adjuvants and antitumor agents.

Diarylation of thiazolopyrimidines by laccase and their in vitro evaluation as antitumor agents

A mild and efficient method was developed for the synthesis of new derivatives of thiazolo[3,2-a] pyrimidin-3(2H)-ones from available starting materials based on the oxidation of catechols to ortho-quinone by Myceliophthora thermophila laccase (Novozym 51,003) and 1,4-addition of active methylene carbon to these in situ generated intermediates in moderate to good yields (35–93%). The structure of the products was confirmed through 1H NMR, 13C NMR, HMBC, HSQC, DEPT-135, and mass spectroscopy techniques. These novel compounds were evaluated as active antitumor agents against human colorectal adenocarcinoma and liver adenocarcinoma cell lines. All compounds displayed potent inhibition activities against the HT-29 cell line with IC50 values of 9.8–35.9 µM, superior to the positive control doxorubicin, and most showed potent anticancer activities against the HepG2 cell line.

Root Bark Extract of Oroxylum indicum Vent. Inhibits Solid and Ascites Tumors and Prevents the Development of DMBA-Induced Skin Papilloma Formation

Oroxylum indicum is a traditionally used plant in Ayurvedic and folk medicines. The plant is useful for the management of gastrointestinal diseases as well as skin diseases. In the present study, we analyzed the antitumor potential of O. indicum in Dalton's lymphoma ascites tumor cells (DLA) and Ehrlich ascites carcinoma (EAC)-induced solid and ascites tumors. Further, the potential of O. indicum extract (OIM) on skin papilloma induction by dimethyl benz(a) anthracene (DMBA) and croton oil was evaluated. The chemical composition of the extract was analyzed using UPLC-Q-TOF-MS. The predominant compounds present in the extract were demethoxycentaureidin 7-O-rutinoside, isorhamnetin-3-O-rutinoside, baicalein-7-O-glucuronide, 5,6,7-trihydroxyflavone, 3-Hydroxy-3',4',5'-trimethoxyflavone, 5,7-dihydroxy-3-(4-methoxyphenyl) chromen-4-one, and 4'-Hydroxy-5,7-dimethoxyflavanone. Treatment with high-dose OIM enhanced the percentage of survival in ascites tumor-bearing mice by 34.97%. Likewise, high and low doses of OIM reduced the tumor volume in mice by 61.84% and 54.21%, respectively. Further, the skin papilloma formation was brought down by the administration of low- and high-dose groups of OIM (by 67.51% and 75.63%). Overall, the study concludes that the Oroxylum indicum root bark extract is a potentially active antitumor and anticancer agent.

SYNTHESIS AND CONVERSION OF NEW POTENTIALLY BIOLOGICALLY ACTIVE 4-THIAZOLIDINONE DERIVATIVES WITH A TRIAZINOINDOLE FRAGMENT IN THE MOLECULES

A wide spectrum of biological activity and the possibility of diverse chemical modification of isatinderivatives prompts the search for new highly active compounds as potential drugs among condensed and noncondensedheterocyclic systems containing the specified molecular "matrix". Studies of 1,2,4-triazino[5,6-b]indoles,the chemical precursors of which are isatins, have shown the prospect of their use in the treatment of oncologicaldiseases. In addition, potential antifungal, antiviral, antihypertensive agents have been identified among thesederivatives.Adhering to the main synthetic strategy of our research, which is based on the "hybrid-pharmacophoric" approach inthe synthesis of new heterocyclic derivatives of 4-thiazolidinone, in our opinion, the combination of the mainscaffold (4-thiazolidinone) and the structural "imitator" is interesting and promising of the isatin "matrix" -triazinoindole fragment, as well as the synthesis of new polyheterocyclic ensembles, including those with apharmacologically attractive pyrazoline fragment. Under the conditions of the S-alkylation reaction of 3-mercapto-5H-1,2,4-triazino[5,6-b]indoles, 2-chloro-1-(3,5-diaryl-4,5-dihydropyrazole- 1-yl)ethanones, which made it possibleto obtain 1,2,4-triazino[5,6-b]indole-pyrazolines with preparative yields. By hydrazinolysis of 3-mercapto-5H-1,2,4-triazino[5,6-b]indoles, corresponding hydrazines were obtained, which were successfully used for the first time inthe Holmberg reaction, and derivatives of the triazinoindole-thiazolidinone system were obtained – 3-(1,2 ,4-triazino[5,6-b]indol-3-ylamino-2-thioxothiazolidin-4-ones Chemical modification of methylene-active compoundswas carried out under the conditions of the Kniovenagel reaction with aromatic aldehydes and isatin derivatives,which was substantiated by the results of biological studies of structurally related heteryl-substituted 5-ylidenerhodanines. The synthesis of derivatives of the 4-thiazolidinone-thiadiazinoindole system, which is based onthe interaction of N-(1,3,4-thiadiazinoindol-2-yl)-2-chloroacetamides with ammonium thiocyanate in an acetonemedium, was carried out. The obtained conjugates are methylene-active compounds, which made it possible tosynthesize a series of 5-arylidene derivatives under the conditions of the Kniovenagel reaction. The purpose of thework is to experimentally confirm or refute the feasibility of chemical modification of isatin into the triazineindolinesystem and its combination with 4-thiazolidinone biophore for the search of new biologically activecompounds, including highly active antitumor agents. The structure of the synthesized compounds was confirmedby NMR spectroscopy. To study the structure in the solid state, the IR spectra of the key compounds in KBr tabletswere studied.

Abstract 667: Inhibition of protein-protein interaction between STING and TRIM29 is a new approach to enhance anti-tumor immune response

Abstract Introduction: STimulator of INterferon Genes (STING) has been reported to be essential for antitumor immunity by inducing type I IFN expression, resulting in activation of both innate and adaptive immunity. Thus, pharmacological activation of STING pathway is actively being tested in many clinical studies. However, the clinical efficacy was not that clear, probably due to the limited expression of STING protein, which is tightly regulated by TRIM29 (E3 ligase)-mediated protein degradation pathway. Here, we present a novel small-molecule drug candidate with strong antitumor response in murine syngeneic model by upregulating cellular levels of STING through the inhibition of protein-protein interaction. Methods: The inhibitors of STING-TRIM29 interaction were identified using luciferase-complementation high-throughput screening system. Target protein of the inhibitor was identified in cellular thermostability shift assay. Their immunological activity was tested in Raw264.7 and A431 cells as well as CT26 murine syngeneic model. Results: The lead compound, SB24011, bound to STING and upregulated cellular levels of STING by inhibiting ubiquitin-mediated degradation. Together with STING agonist, SB24011 synergistically enhanced the inflammatory cytokine expression in cell lines as well as in CT26 syngeneic animal model. Intratumoral injection of SB24011 showed strong abscopal activity as single agent as well as synergistic antitumor responses with anti-PD1 antibody in CT26 syngeneic animal model. Conclusions: We identified novel small-molecule drug candidate, SB24011, which prevents the degradation of both murine and human STING proteins, resulting in enhanced immune responses together with STING agonist, cGAMP. SB24011 showed strong abscopal antitumor activity as single agent and synergistic antitumor activity as combination agent with other IO agents in CT26 syngeneic models. Citation Format: Seung Bum Park, Wansang Cho, Won Sol Chan, young il choi, Sungoh Ahn, Dong-Sup Lee. Inhibition of protein-protein interaction between STING and TRIM29 is a new approach to enhance anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 667.

Apoptotic Effect of Novel Benzimidazole Derivatives Bearing Pyridyl/Pyrimidinyl Piperazine Moiety.

Benzimidazole derivatives bearing pyridyl/pyrimidinyl piperazine moiety has attracted attention in medicinal chemistry and modern drug discovery since it exhibited a variety of biological activities, including anticancer activity. In this study, we designed and synthesized novel 1-[2-oxo-2-(4-substituted phenyl)ethyl]benzimidazol-2- yl)methyl 4-(2-pyridyl/pyrimidin-2-yl)piperazine-1-carbodithioate derivatives (2a-m). We also investigated their anticancer activities against A549 lung adenocarcinoma and C6 rat glioma cell lines. We further studied the selectivity of the compounds against the NIH/3T3 mouse embryonic fibroblast cell line. Cholinesterase inhibition effects of these compounds were also investigated to measure the relationship between anticancer activity and cholinesterases. The cytotoxic activities of these acquired thirteen final compounds were screened using MTT assay on A549, C6, and NIH/3T3 cell lines. Cell proliferation ELISA, BRDU (colorimetric) assay was used to measure the proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analysis was used to measure apoptotic cell percentages, caspase 3 activity, and mitochondrial membrane depolarised cell percentages. Compounds 2e, 2f, and 2k were shown to be the most active antitumor agents with selective cytotoxicities (the results for A549 were 76.58±6.43, 55.13±5.75, and 32.94±3.02 μM, respectively; and for C6 they were 86.48±3.60, 97.12±30.21, and 59.29±3.95 μM, respectively), high DNA synthesis inhibition rates and high apoptotic cell percentages on both cell lines. The results showed that compounds 2e, 2f, and 2k have potential anticancer activity against A549 and C6 cell lines.

Evodiamine-Inspired Topoisomerase-Histone Deacetylase Dual Inhibitors: Novel Orally Active Antitumor Agents for Leukemia Therapy.

On the basis of the synergism of topoisomerase (Top) and histone deacetylase (HDAC) inhibitors in antitumor therapy, a series of novel Top/HDAC dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. After systematic structure-activity relationship studies, lead compound 16j was identified to simultaneously inhibit both Top and HDAC with good potency, which showed potent antiproliferative activities with a broad spectrum. Mechanistic studies indicated that compound 16j efficiently induced apoptosis with S cell-cycle arrest in HEL cancer cells. It was orally active in HEL xenograft models and exhibited excellent in vivo antitumor efficacy (TGI = 68.5%; 10 mg/kg). Altogether, this work highlights the therapeutic potential of evodiamine-inspired Top/HDAC dual inhibitors and provides a valuable lead compound for the development of novel antitumor agents for leukemia therapy.

Design, synthesis, antitumor, and VEGFR-2 inhibition activities of novel 4-anilino-2-vinyl-quinazolines: Molecular modeling studies

The antitumor activity of newly synthesized 4-anilino-2-vinylquinazolines 8a-r was measured comparable to sorafenib as a standard drug. The 2-vinylquinazolines 8a-r were evaluated for their in vitro antitumor activity. The most active antitumor agents were subjected to in vitro VEGFR-2 inhibition and apoptotic inducing assay. Compounds 8 h, 8 l, and 8r showed potential antitumor activities with IC50 values of 4.92–14.37 μM relative to the reference drug, sorafenib (IC50 values of 5.47–9.18 μM). Compound 8 h possessed potential VEGFR-2 inhibitory activity (IC50 = 60.27 nM) compared to standard drug sorafenib (IC50 = 55.43 nM), whereas compound 8 l showed moderate inhibitory activity (IC50 = 93.50 nM). The most active compound, 8 h, exhibited total apoptosis with 36.24% on MCF-7 cells, more than the apoptotic effect provoked by sorafenib (32.46%) and the cell cycle arrested at a G1/S phase. Compound 8 h, a potent VEGFR-2 inhibitor, was docked into the VEGFR-2 binding pocket, where this compound showed binding interaction similar to co-crystallized inhibitor sorafenib.

Combination Therapy Strategy for Lymphoma Based on Cancer Energy Metabolism of OPB-111077, a Novel Antitumor Agent Inhibiting Mitochondrial Oxidative Phosphorylation

Development of antitumor agents targeting energy metabolism pathways of cancer cells has attracted much attention in recent days. In general, most cancer cells are known to display Warburg effect. Recently, it has been reported that cancer cells exist as heterogeneous groups in the microenvironment surrounding cancer cells and that not only glycolysis but also mitochondrial oxidative phosphorylation (OXPHOS) is important for cancer growth. In addition, many research groups have reported that the acquisition of anticancer drug resistance is caused by metabolic reprogramming from glycolysis to OXPHOS. Therefore, OXPHOS inhibitors could be useful antitumor agents. OPB-111077 is an orally active novel antitumor agent and has the inhibitory effect on mitochondrial OXPHOS. OPB-111077 had the inhibitory effect on mitochondrial respiratory chain complex I which led to the inhibition of energy production and activation of AMPK-mTOR energy stress sensor pathway. In in vitro growth inhibition studies, OPB-111077 showed potent inhibitory effects on the growth of various human blood tumor cell lines derived from leukemia, multiple myeloma and lymphoma with IC 50 values between 18.6 and 525.3 nM, and on the growth of human solid tumor cell lines derived from liver cancer, lung cancer, gastric cancer and breast cancer with IC 50 values ranging from 92.6 to 1727.7 nM. In in vivo studies using SCID mice bearing tumors from human tumor cell lines, daily oral administration of OPB-111077 demonstrated significant antitumor effects against leukemia, lymphoma, liver, gastric and breast cancer cell line-derived tumor, dose-dependently.Here, we report the combination therapy strategy based on the cancer energy metabolism of OPB-111077. We found that OPB-111077 combined with alkylating agent, cyclophosphamide or bendamustine, showed the synergistic effect on xenograft mice model using human diffuse large B‐cell lymphoma (DLBCL) cell line. To clarify this mechanism, we examined the effect of alkylating agents on mitochondrial respiration in vitro using flux analyzer and found that alkylating agents induced OXPHOS nature in the DLBCL cell line. Furthermore, the administration of alkylating agents to DLBCL cell line xenograft model mice followed by mRNA expression analysis of their tumor tissue confirmed that expression of OXPHOS-related markers was induced. These results suggest the administration of alkylating agents induced reprogramming to OXPHOS predominant nature in tumor. The tumor environment is actively reprogrammed to OXPHOS by alkylating agents, and it is changed to a state in which the antitumor effect of OPB-111077 can be more exerted. Thus, alkylating agents enhance the effect of OPB-111077 by tilting glycolytically dominant tumors to OXPHOS dominant. The alkylating agents, cyclophosphamide and bendamustine, are used as standard therapies for lymphoma. OPB-111077 could be treated in a wide range of applications as a combination therapy with the alkylating agents for lymphoma.In clinical, we have confirmed that OPB-111077 has tolerable and controllable toxicity profile of single agent in some advanced cancer patients including DLBCL. Bendamustine and rituximab (BR) therapy is indicated for the treatment of patients who are ineligible for transplantation of relapsed / refractory (R/R) DLBCL. However, there is still a high unmet need for patients with R/R DLBCL due to no standard treatment for transplant‐ineligible patients. We are conducting combination therapy of OPB-111077 with bendamustine and rituximab in Phase 1 clinical trial for R/R DLBCL in Japan. DisclosuresOhi: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. Okuno: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. Tanaka: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. Ohtani: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. OffLabel Disclosure:Compound: OPB-111077 Purpose: Development of novel antitumor agent

Debulking before Initiation of Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Results from a Phase 3b Study

Debulking before Initiation of Venetoclax Therapy in Untreated Patients with Chronic Lymphocytic Leukemia: Results from a Phase 3b Study

RARE-08. POTENTIAL NEW THERAPIES FOR DIFFUSE INTRINSIC PONTINE GLIOMAS IDENTIFIED THROUGH HIGH THROUGHPUT DRUG SCREENING

Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12-months. There is an urgent need for novel effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,570 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds - auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine - that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in vitro. To determine whether the in vitro efficacy could be replicated in vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide, auranofin and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different fenretinide formulations which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG.

Confinement of the antitumoral drug cisplatin inside edge-functionalized carbon nanotubes and its release near lipid membrane

Platinum complexes are active antitumor agents. They are widely used in chemotherapy medication for the treatment of several cancer types. Unfortunately, these drugs present poor stability when administered and have several side effects, damaging healthy cells around the tumor. One way to remedy the damage is to confine drug molecules in carbon cages such as carbon nanotubes (CNTs) before delivering them near their target cells. In order to open their ends, the CNTs must be functionalized by oxidation. This leads to the saturation of the carbon dangling bonds with an alcohol functional group, for instance. In this study, molecular dynamics simulations are carried out to assess the influence of CNT’s chemical functional groups (–H, –OH, –COOH) on the retention time and release processes of cisplatin molecules throughout the process of vectorization to a cell membrane.

Discovery of an orally active antitumor agent that induces apoptosis and suppresses EMT through heat shock protein 90inhibition.

Background Nowadays, lung cancer seriously affects human health in the world. Therefore, it is of great significance to develop effective anti-lung cancer drugs. Methods In this work, chalcone derivative HYQ97 was designed via a molecular hybridization strategy. It was synthesized by the cycloaddition in the presence of sodium ascorbate under mild conditions. Lung cancer cell lines were cultured to investigate its antitumor effects in vitro and in vivo. Results HYQ97 inhibited the proliferation of lung cancer cell lines. Specifically, its IC50 value against lung cancer A549 cells was 74.26 nM. It could inhibit heat shock protein 90 (Hsp90) and degrade its client proteins in a dose-dependent manner. Furthermore, HYQ97 suppressed the epithelial mesenchymal transition process and induced apoptosis of A549 cells. Importantly, HYQ97 also had significant inhibitory effects on tumor growth in vivo. Conclusions Chalcone derivative HYQ97 is a promising candidate for lung cancer treatment.

Transition metal (II) complexes of hydrazones derived from tetralone: synthesis, spectral characterization, in vitro antimicrobial and cytotoxic studies

A series of transition metal (II) complexes with general formula [M(L1−4)2(H2O)2] (where M = Co(II), Ni(II), Cu(II) and Zn(II)) was synthesized by the reaction of metal(II) acetates with hydrazones [HL1–HL4] obtained from condensation of tetralone with hydrazide derivatives. The characterization of synthesized compounds (1–20) was done by using elemental analysis, different spectral studies (UV–Vis, 1H NMR, 13C NMR, FT-IR, mass, ESR and fluorescence), magnetic susceptibility, molar conductance measurement and thermal (DTA, TGA and DTG) analysis. The characterization results suggested the bidentate nature of the hydrazones, which chelate with the metal ion via nitrogen of (C=N) group and deprotonated carbonyl oxygen in the enolized form, resulting in stable, non-volatile octahedral complexes. The antimicrobial potential of the compounds was evaluated against four bacterial, i.e. (S. aureus, B. subtilis, P. aeruginosa and E. coli), and two fungal species, i.e. (A. niger and C. albicans), by a serial dilution method with complexes 15 and 16 as most active compounds against microbes. All the compounds were also tested for its cytotoxicity (in vitro) against three human cancer cell lines (A549, HeLa and MCF-7) and one normal cell line (L6) by the MTT assay, which focussed on an increased activity of compounds 7 and 15 towards A549, MCF-7 and HeLa cancer cell line with IC50 values ranging from 10.76 to 16.42 μg/mL, and compounds were found to be non-toxic towards L6 cell line as compared to the standard drug doxorubicin. The results demonstrated that complexation enhanced the biological activity of compounds. The synthesized compounds (1–20) were screened for antitumor activities against A549, MCF7, Hela cancer cell lines. Copper complex (7) and (15) was found to be the most active antitumor agent and less toxic against L6—Rat myoblast normal cell line than standard doxorubicin.

DIPG-07. HIGH THROUGHPUT DRUG SCREENING IDENTIFIES POTENTIAL NEW THERAPIES FOR DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGs)

DIPGs are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12 months. There is an urgent need for novel effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,500 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds- auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine- that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in-vitro. To determine whether the in-vitro efficacy could be replicated in-vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different Fenretinide formulations (LYM-X-Sorb and NanoMicelle) which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG.

Discovery of tofacitinib derivatives as orally active antitumor agents based on the scaffold hybridization strategy

In this work, a novel series of tofacitinib analogs were designed and synthesized based on the scaffold hybridization strategy and then evaluated for their antiproliferative activity toward three gastric cancer cell lines, leading to the identification of compound C18 which exhibited potent inhibitory activity against MGC-803 cell lines with an IC50 value of 2.68 μM. Compound C18 could effectively inhibit the colony formation, suppress the cell migration and induce apoptosis of MGC-803 cells through activating the p38 and JNK signaling pathways, while C18 showed no obvious effect on the cell cycle distribution in MGC-803 cells. In addition, C18 could initiate mitochondrial dysfunction of MGC-803 cells. Besides, in vivo antitumor studies indicated that C18 could inhibit gastric cancer tumor growth in vivo without obvious global toxicity.

A combinatorial approach involving E. coli cytosine deaminase and 5-fluorocytosine-nanoparticles as an enzyme-prodrug therapeutic method for highly substrate selective in situ generation of 5-fluorouracil

Enzyme-prodrug combination is a recognized therapeutic strategy for the treatment of cancer cells. Cytosine deaminases (CD) are non-mammalian proteins perceived to convert the prodrug 5-fluorocytosine (5-FC), into the active antitumor agent 5-fluorouracil (5-FU). In this study, we have synthesized 5-FC as well as 5-FU loaded chitosan-silver nanoparticles in a green synthesis approach, with high yield. The size of the nanoparticles was ascertained to be below 25 nm, thus proficient in penetrating cells. Investigation in human breast carcinoma cell line MDA-MB-468 manifested potent cytotoxicity for 5-FU nanoparticles as compared to the prodrug, 5-FC nanoparticles. E. coli CD (ECD) effectively hydrolyzes 5-FC into 5-FU but was inert to silver nanoparticles as well as 5-FU loaded nanoparticles.

Combined therapy of oncolytic Newcastle disease virus and rhizomes extract of Rheum ribes enhances cancer virotherapy in vitro and in vivo.

Phytotherapy has been used to treat a different type of diseases including cancer for a long time, and it was a source for different active anti-tumor agents. Oncolytic Newcastle disease virus (AMHA1) are very promising anti-tumor therapy. Nevertheless, NDV-based monotherapeutics have not been very useful to some resistant tumors. Thus, the efficiency of oncolytic NDV must enhance by combining NDV with other novel therapies. The current study aimed to determine the possibility of improving the oncolytic effect induced by NDV through Rheum ribes rhizomes extract administration in vitro and in vivo. Methods, the in vitro study include exposure of the crude extract of Rheum ribes alone or NDV alone or combination of both agents for 72h. The cancer cells tested were murine mammary adenocarcinoma AMN3, Human Rhabdomyosarcoma RD, and Human Glioblastoma AMGM5, and using rat embryo fibroblast REF as normal control cells. MTT cell viability assay was used and analyzed for possible synergism using the Chou-Talalay analysis method. In vivo experiment included study the combination and the monotherapeutic modalities in the transplanted murine mammary adenocarcinoma AM3 line and tumor sections analyzed by histopathology. Results, Combination therapy of NDV-R. ribes showed enhanced oncolytic activity on cancer cells. With no cytotoxicity on normal cells. In vivo study showed that monotherapeutic modalities had lower growth inhibitory effect on transplanted tumors in mice in compare to combination therapy. Histopathological examination revealed the broader area of necrosis in tumors treated by combination therapy. In conclusion, the novel combination recommended for clinical application for cancer therapy.

Discovery of a Novel, Highly Potent, and Selective Thieno[3,2-d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent.

In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.