Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors.

ABSTRACT: Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of ?-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

SUBMITTER: Gavai AV

PROVIDER: S-EPMC4434460 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors.

Gavai Ashvinikumar V AV Quesnelle Claude C Norris Derek D Han Wen-Ching WC Gill Patrice P Shan Weifang W Balog Aaron A Chen Ke K Tebben Andrew A Rampulla Richard R Wu Dauh-Rurng DR Zhang Yingru Y Mathur Arvind A White Ronald R Rose Anne A Wang Haiqing H Yang Zheng Z Ranasinghe Asoka A D'Arienzo Celia C Guarino Victor V Xiao Lan L Su Ching C Everlof Gerry G Arora Vinod V Shen Ding Ren DR Cvijic Mary Ellen ME Menard Krista K Wen Mei-Li ML Meredith Jere J Trainor George G Lombardo Louis J LJ Olson Richard R Baran Phil S PS Hunt John T JT Vite Gregory D GD Fischer Bruce S BS Westhouse Richard A RA Lee Francis Y FY

ACS medicinal chemistry letters 20150311 5

Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation. ...[more]

PMID: 26005526

Similar Datasets

Discovery of a highly potent, orally active mitosis/angiogenesis inhibitor r1530 for the treatment of solid tumors.

Project description:A new series of 7,8-disubstituted pyrazolobenzodiazepines based on the lead compound 1 have been synthesized and evaluated for their effects on mitosis and angiogenesis. Described herein is the design, synthesis, SAR, and antitumor activity of these compounds leading to the identification of R1530, which was selected for clinical evaluation.

| S-EPMC4027509 | biostudies-literature

Radiosensitization of solid tumors by Z-VAD, a pan-caspase inhibitor.

Project description:Despite recent advances in the management of breast and lung cancer, novel treatment strategies are still needed to further improve patient outcome. The targeting of cell death pathways has therefore been proposed to enhance therapeutic ratio in cancer. In this study, we examined the in vitro and in vivo effects of Z-VAD, a broad-spectrum caspase inhibitor, on breast and lung cancer in association with radiation. Using clonogenic assays, we observed that Z-VAD markedly radiosensitized breast and lung cancer cells, with a radiation dose enhancement ratio of 1.31 (P < 0.003). For both models, the enhanced tumor cytotoxicity was associated with induction of autophagy. Furthermore, we found that administration of Z-VAD with radiation in both breast and lung cancer xenograft produced a significant tumor growth delay compared with radiation alone and was well tolerated. Interestingly, Z-VAD also had dramatic antiangiogenic effect when combined with radiation both in vitro and in vivo and thus represents an attractive anticancer therapeutic strategy. In conclusion, this preclinical study supports the therapeutic potential of Z-VAD as a radiosensitizer in breast and lung cancer. This study also suggests caspase inhibition as a promising strategy to enhance the therapeutic ratio of radiation therapy in solid tumors. Therefore, clinical trials are needed to determine the potential of this combination therapy in cancer patients.

| S-EPMC2888880 | biostudies-literature

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor.

Project description:During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aβ40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

| S-EPMC4007960 | biostudies-literature

Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor.

Project description:For a subpopulation of acute myeloid leukemia (AML) patients, the mutationally activated tyrosine kinase FLT3, has emerged as a promising target for therapy. The development of drug resistance due to mutation is a growing concern for mutant FLT3 inhibitors, such as PKC412, Quizartinib, PLX3397, and Crenolanib. Thus, there is a need to develop novel FLT3 inhibitors that overcome these mutations. Here we report the development of a novel type I ATP competitive inhibitor, JH-IX-179, that is extremely potent and selective for FLT3. JH-IX-179 also has the highest affinity for three constitutively active isoforms of FLT3 (FLT3-ITD, FLT3-N841I, and FLT3-D835V) compared to a panel 456 other kinases. The unique and specific kinase inhibition profile suggests that this chemotype may represent an attractive starting point for the development of further improved FLT3 inhibitors with therapeutic potential in tumors harboring deregulated FLT3 activity.

| S-EPMC4867484 | biostudies-literature

Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGF?R1 Inhibitor as an Immuno-oncology Agent.

Project description:Novel imidazole-based TGF?R1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGF?R1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGF?-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGF?R1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

| S-EPMC7025382 | biostudies-literature

Discovery of CX-6258. A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor.

Project description:Structure-activity relationship analysis in a series of 3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)amides identified compound 13, a pan-Pim kinases inhibitor with excellent biochemical potency and kinase selectivity. Compound 13 exhibited in vitro synergy with chemotherapeutics and robust in vivo efficacy in two Pim kinases driven tumor models.

| S-EPMC4025662 | biostudies-literature

A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours.

Project description:Background Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling. Method Two dose escalation schedules (Arm-A continuous daily schedule and Arm-B intermittent 2 times weekly schedule) of BMS-986115 were evaluated in advanced solid tumour patients. The primary objective was to establish the safety, tolerability and Maximum Tolerated Dose (MTD) of BMS-986115. Results Thirty six patients (24 in Arm A and 12 in Arm B) were treated. The most frequent treatment related adverse advents were diarrhoea (72%), hypophosphataemia (64%), and nausea (61%). The MTD was 1.5 mg daily in Arm A but not established in Arm B. Four patients in Arm A and 2 in Arm B experienced dose limiting toxicities (grade 3 nausea, diarrhoea, pruritus/urticaria and ileus). BMS-986115 showed dose related increase in exposure within the dose range tested. Target inhibition of Notch pathway related genes was observed. Three patients in Arm A and 2 in Arm B achieved stable disease for more than 6 months. Conclusion The daily oral dosing of BMS-986115 is safe and tolerable with biological activity demonstrated by continuous target engagement and Notch signalling inhibition.

| S-EPMC7523345 | biostudies-literature

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors.

Project description:PurposePatients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system.Experimental designWe developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models.ResultsB7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3.ConclusionsB7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.

| S-EPMC8456711 | biostudies-literature

Dasatinib: a potent SRC inhibitor in clinical development for the treatment of solid tumors.

Project description:SRC is a tyrosine kinase that plays a role in oncogenic, invasive and bone-metastatic processes. It has therefore been prioritized as a candidate therapeutic target in patients with solid tumors. Several SRC inhibitors are now in development, of which dasatinib has been most explored. Preclinical studies in a wide variety of solid tumor cell lines, including prostate, breast and glioma, have shown that that dasatinib acts as a cytostatic agent, inhibiting the processes of cell proliferation, invasion and metastasis. Dasatinib also inhibits the activity of osteoclasts, which have a major role in the development of metastatic bone lesions. Dasatinib has additive or synergistic activity in combination with a number of other agents, including cytotoxic agents and targeted therapies, providing a rationale for combination treatment in a clinical setting. Emerging clinical data with dasatinib support experimental observations, with preliminary phase 1 and 2 data demonstrating activity, both as a single agent and as combination therapy, in a range of solid tumors. Future clinical trials will further assess the clinical value of SRC inhibition with dasatinib.

| S-EPMC3940067 | biostudies-literature

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

Project description:PURPOSE:This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K). PATIENTS AND METHODS:Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue. RESULTS:Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 h·?mol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively. CONCLUSION:Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels ?100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.

| S-EPMC4287394 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data