Mei-Li Wen

BMS-871: A novel orally active pan-Notch inhibitor as an anticancer agent

This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.

Abstract 1643: BMS-983970, an oral pan-Notch inhibitor for the treatment of cancer

Deregulation of the Notch pathway has been shown to be oncogenic in numerous tissue types including T-cell acute lymphoblastic leukemia (T-ALL), breast cancer, non-small cell lung cancer, and colorectal carcinoma. Notch signal activation can cause uncontrolled proliferation, restrict differentiation leading to increased self-renewal capacity, evasion of apoptosis, and enhancement of angiogenesis and metastasis. There is increasing evidence that Notch plays a role in the maintenance and survival of cancer stem cells. γ-Secretase mediates the Notch signaling pathway by releasing the Notch intracellular domain (NICD) which translocates to the nucleus and binds to the transcription factor CSL to activate transcription of various target genes. BMS-906024 is a potent pan-Notch inhibitor that demonstrated robust anti-tumor activity at tolerated doses in multiple tumor xenograft models. It is being evaluated in Phase 1 clinical studies. BMS-906024 is being administered IV (once weekly) in the clinic and the projected human efficacious dose is 4 - 6 mg. Based on the preclinical data, the projected human half-life of BMS-906024 is in the 37 h - 124 h range. This presentation will describe further structure-activity relationships in the 1,4-benzodiazepinone series that culminated in the identification of BMS-983970 as an oral-pan-Notch inhibitor. Pharmacokinetic properties and in vivo evaluation of BMS-983970 in T-ALL and solid tumor xenograft models will be presented. Citation Format: Ashvinikumar V. Gavai, Yufen Zhao, Daniel O9Malley, Brian Fink, Claude Quesnelle, Derek Norris, Libing Chen, Soong-Hoon Kim, Wen-Ching Han, Patrice Gill, Weifang Shan, Aaron Balog, Andrew Tebben, Richard Rampulla, Dauh-Rurng Wu, Yingru Zhang, Arvind Mathur, Haiqing Wang, Zheng Yang, Qian Ruan, Robin Moore, David Rodrigues, Asoka Ranasinghe, Celia D9Arienzo, Ching Kim Tye, Ching Su, Gerry Everlof, Melissa Yarde, Mary Ellen Cvijic, Krista Menard, Mei-Li Wen, George Trainor, Bruce Fischer, John Hunt, Gregory Vite, Richard Westhouse, Francis Lee. BMS-983970, an oral pan-Notch inhibitor for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2014-1643

Abstract B195: Synergy between ixabepilone (Ixa) and trastuzumab (TZ): Investigation of the role of microtubule‐associated protein (MAP‐tau) and III tubulin (βIII) in HER2‐positive (HER2+) breast cancer (BC)

Background and rationale: Historically, patients with aggressive HER2+ BC have a poor response to chemotherapy, including antimicrotubule agents. Elevated III levels have been reported in HER2+ BC. Introduction of the HER2+ targeted agent TZ, in combination with taxane based chemotherapy, greatly improved the outcomes of these patients. The novel antimicrotubule agent Ixa has broad preclinical and clinical efficacy in BC tumors, including those that overexpress III, a predictor of taxane resistance. Previous reports in BC cell lines and tumors have shown an inverse correlation between Ixa/taxane sensitivity and MAP‐tau. We set out to evaluate the activity of Ixa in combination with TZ and explore the relationship between III and MAPtau expression and Ixa response in HER2+ BC. Here we provide preclinical evidence of synergy with Ixa plus TZ and preclinical and clinical evidence of the contribution of MAP‐tau and III in HER2+ BC. Methods: In preclinical studies with HER2+ human BC cell lines BT‐474 and KPL‐4 the effects of drug exposure were determined by a vital dye uptake assay (MTS) or a colony formation assay. Gene (Affymetrix HG U133A v2.0 Gene Chips) and protein expression (immunoblotting) changes in cells exposed to TZ or estradiol (E2; control) were assessed. BT‐474 and KPL‐4 subcutaneous tumors in mice were also assessed. Using intrinsic gene clustering, microarray expression data from 134 breast tumors from the Ixa monotherapy neoadjuvant BC trial CA163‐080 (080) were subtyped as HER2‐enriched, basal‐, luminal‐ or normal‐like, and III/MAP‐tau expression was assessed by subtype. Results: Ixa exhibited synergistic activity in combination with TZ in vitro (HER2+ BT‐474 cell line). Synergy was also demonstrated in BT‐474 and KPL‐4 human BC xenografts in mice; 75% complete response (CR) was achieved in BT‐474, compared with 0% CR and 25% partial response (PR) with Ixa alone, and 0% CR and 0% PR with TZ alone. Exposure of BT‐474 cells to TZ for 24 hours caused down regulation of MAP‐tau, relative to E2. Analysis of clinical tumor samples from 080 demonstrated that HER2‐enriched tumors have elevated III, but reduced MAP‐Tau levels relative to luminal‐like and normal‐like subtypes (P Conclusions: Ixa and TZ demonstrated synergy in HER2+ BC models. The ability of TZ to down regulate MAP‐tau may explain, at least partially, the synergistic activity seen in the clinical setting when TZ is combined with antimicrotubule agents. Retrospective analysis of the 080 trial revealed that III was over‐ and MAP‐tau was under‐expressed, in HER2‐enriched tumors relative to other BC subtypes. In two Phase 2 studies, Ixa was safe and effective when combined with TZ for the treatment of HER2+ BC patients. This data supports further exploration of III/MAP‐tau expression and Ixa response in HER2+ BC in the clinical setting. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B195.