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

Gavai, Ashvinikumar V.; Quesnelle, Claude; Norris, Derek; Han, Wen-Ching; Gill, Patrice; Shan, Weifang; Balog, Aaron; Chen, Ke; Tebben, Andrew J.; Rampulla, Richard; Wu, Dauh‐Rurng; Zhang, Yingru; Mathur, Arvind; White, Ronald J.; Rose, Anne; Wang, Haiqing; Yang, Zheng; Ranasinghe, Asoka; D’Arienzo, Celia; Guarino, Victor R.; Xiao, Lan; Su, Ching; Everlof, Gerry; Arora, Vinod; Shen, Ding Ren; Cvijic, Mary Ellen; Menard, Krista; Wen, Mei‐Li; Meredith, Jere E.; Trainor, George L.; Lombardo, Louis J.; Olson, R. E.; Baran, Phil S.; Hunt, John T.; Vite, Gregory D.; Fischer, Bruce S.; Westhouse, Richard A.; Lee, Francis Y.

doi:10.1021/acsmedchemlett.5b00001

Cited by 82 publications

(50 citation statements)

References 12 publications

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“…It was previously reported that BMS-906024 potently inhibits the activation of all four Notch receptors (20). To determine the optimal concentration of BMS-906024 that inhibits the presenilin gamma secretase complex in NSCLC, we measured activated Notch1 ICD protein levels.…”

Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

“…BMS-906024 demonstrated a low nanomolar half maximal concentration (IC 50 ) in in vitro enzyme assays and cellular Notch reporter assays (20, 21). Oral administration of BMS-906024 in mice bearing T-ALL or breast cancer xenografts resulted in dose-dependent inhibition of tumor growth, with no overt toxicity observed in dosages up to 6 mg/kg (20). Three Phase 1 clinical trials utilizing BMS-906024 for leukemia and solid tumors have completed the enrollment of patients (clinicaltrials.gov: NCT01292655, NCT01363817, and NCT01653470) and the safety, tolerability and efficacy are being assessed.…”

Section: Introductionmentioning

confidence: 99%

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Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Morgan

Fischer

Lee

et al. 2017

Molecular Cancer Therapeutics

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Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor (GSI), and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin (mean CI value = 0.54 and 0.85, respectively, P = 0.01). On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI = 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line- and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel, and that wildtype KRAS and BRAF status may predict better patient response to the combination therapy.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Morgan

Fischer

Lee

et al. 2017

Molecular Cancer Therapeutics

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“…For BMS-906024, the accuracy was mostly within 85 to 115% in QC samples containing up to ∼30% of hemolyzed blood, with a slight trend toward decreasing accuracy starting from 20% of hemolyzed blood. Nevertheless, it met the acceptance criteria based on the Bioanalytical Guidance from US FDA and EU EMA guideline (18,26). The same trends were observed for BMS-911557.…”

Section: Effect Of Hemolysis On the Internal Standard Responses Accumentioning

confidence: 52%

“…BMS-906024 (Fig. 1a) is currently being developed for treatment of cancer (26), and BMS-911557 is its metabolite (Fig. 1b).…”

Section: Introductionmentioning

confidence: 99%

Utilizing Internal Standard Responses to Assess Risk on Reporting Bioanalytical Results from Hemolyzed Samples

Fung

Aubry

Allentoff

et al. 2015

AAPS J

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Abstract. Bioanalytical analysis of toxicokinetic and pharmacokinetic samples is an integral part of small molecule drugs development and liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been the technique of choice. One important consideration is the matrix effect, in which ionization of the analytes of interest is affected by the presence of co-eluting interfering components present in the sample matrix. Hemolysis, which results in additional endogenous components being released from the lysed red blood cells, may cause additional matrix interferences. The effects of the degree of hemolysis on the accuracy and precision of the method and the reported sample concentrations from hemolyzed study samples have drawn increasing attention in recent years, especially in cases where the sample concentrations are critical for pharmacokinetic calculation. Currently, there is no established procedure to objectively assess the risk of reporting potentially inaccurate bioanalytical results from hemolyzed study samples. In this work, we evaluated the effect of different degrees of hemolysis on the internal standard peak area, accuracy, and precision of the analyses of BMS-906024 and its metabolite, BMS-911557, in human plasma by LC-MS/MS. In addition, we proposed the strategy of using the peak area of the stable isotope-labeled internal standard (SIL-IS) from the LC-MS/MS measurement as the surrogate marker for risk assessment. Samples with peak areas outside of the pre-defined acceptance criteria, e.g., less than 50% or more than 150% of the average IS response in study samples, plasma standards, and QC samples when SIL-IS is used, are flagged out for further investigation.KEY WORDS: hemolyzed sample/haemolyzed sample; hyperlipemic sample; internal standard peak area/internal standard responses; LC-MS/MS; regulated bioanalysis; risk assessment.

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Benzodiazepines

2018

Privileged Structures in Drug Discovery

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

Cited by 82 publications

References 12 publications

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Utilizing Internal Standard Responses to Assess Risk on Reporting Bioanalytical Results from Hemolyzed Samples

Benzodiazepines

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