Development of a dual small-molecule BCl-XL/BCL-2 inhibitor for non-small cell lu

描述（由申请人提供）：BCL2L1 （BCL-XL）和MCL1在实体肿瘤中经常扩增，包括NSCLC。NSCLC对BCL-XL或MCL-1的依赖性已经通过针对这些分子的遗传和分子方法得到证实。虽然目前最好的小分子BCL-2/BCL-XL抑制剂ABT-263已经在BCL-2驱动的肿瘤（如慢性淋巴细胞白血病）中显示出临床疗效，但它在实体肿瘤中的活性非常有限，部分原因是它在细胞背景下对BCL-XL的拮抗效果较差。因此，迫切需要能够有效拮抗细胞BCL-XL和/或MCL-1的新型小分子，以开发高效的癌症治疗药物。本申请的目的是确定BM-1197的治疗潜力，BM-1197是一种最近发现的高效小分子BCL-XL/BCL-2抑制剂，用于治疗非小细胞肺癌。核心假设是BM-1197作为单一药物对BCL-XL成瘾的非小细胞肺癌亚群具有很强的抗肿瘤活性，并且当与可以中和MCL-1的药物联合使用时，在非小细胞肺癌中表现出更广泛的抗肿瘤活性。这一假设是基于令人兴奋的初步研究，这些研究表明BM-1197:(1)在多种细胞系模型中，通过靶向BCL- xl和BCL- 2有效诱导细胞凋亡；(2)即使每周给药，异种肿瘤移植模型也能实现完全和持续的肿瘤消退；(3)引起小鼠短暂性血小板减少，但其他方面耐受性良好；(4)在BCL2L1扩增的非小细胞肺癌细胞系中表现出强有力的抑制活性；(5)与多西他赛和最近fda批准的MEK抑制剂曲美替尼在很大比例的NSCLC细胞系中实现强大的协同作用；(6)在直接比较中，比ABT-263在体外更有效，在体内更有效。为了实现将BM-1197作为一种新的、有效的、个性化的非小细胞肺癌药物的最终目标，我们将追求三个特定的目标：1)在体外和体内确定BM-1197作为单一药物在非小细胞肺癌中的抗肿瘤活性，并确定其敏感性的分子决定因素；2)确定bm -1197-多西他赛联合治疗NSCLC的体内外作用机制、抗肿瘤活性及潜在毒性；3)确定bm -1197-曲美替尼联合用药在NSCLC体内外的作用机制、抗肿瘤活性和潜在毒性。将采用多种互补的临床前模型，包括大量具有良好特征的非小细胞肺癌细胞系、细胞系衍生的异种移植物和小鼠非小细胞肺癌患者衍生的异种移植物。该项目旨在建立BM-1197在非小细胞肺癌临床前模型中的强抗肿瘤活性，并确定在单药和联合用药情况下BM-1197敏感性的关键分子决定因素。BM-1197正在进行ind研究，不久将进入临床试验。因此，本项目的成功将对BM-1197转化为治疗NSCLC的新疗法产生重大影响。确定BM-1197敏感性的分子决定因素将极大地促进BM-1197作为一种新的非小细胞肺癌个性化治疗方法的发展。

DESCRIPTION (provided by applicant): BCL2L1 (BCL-XL) and MCL1 are frequently amplified in solid tumors, including NSCLC. The addiction of NSCLC to BCL-XL or MCL-1 has been demonstrated by genetic and molecular approaches targeting these molecules. Although ABT-263, the current best small-molecule BCL-2/BCL-XL inhibitor, has demonstrated clinical efficacy in BCL-2-driven tumors, such as chronic lymphocytic leukemia, it has very limited activity in solid tumors, partially due to its less effectiveness in antagonizing BCL-XL in cellula context. Therefore, there is a critical need for novel small-molecules that can effectively antagonize cellular BCL-XL and/or MCL-1 for the development of highly effective cancer therapeutics. The objective of this application is to determine the therapeutic potential of BM-1197, a recently discovered highly potent small-molecule BCL-XL/BCL-2 inhibitor, for the treatment of NSCLC. The central hypothesis is that BM-1197 possesses strong antitumor activity as a single-agent against a subset of NSCLC addicted to BCL-XL, and exhibits a much broader antitumor activity in NSCLC when combined with drugs that can neutralize MCL-1. This hypothesis is based on the exciting preliminary studies, which show that BM-1197: (1) effectively induces apoptosis by targeting BCL-XL and BCL- 2 in a variety of cell line models; (2) achieves complete and persistent tumor regression in tumor xenograft models even with weekly dosing; (3) causes transient platelet reduction in mice, but otherwise is well-tolerated; (4) exhibits potent inhibitory activity in NSCLC cell lines with amplified BCL2L1; (5) achieves strong synergy with docetaxel and the recently FDA-approved MEK inhibitor trametinib in a significant proportion of NSCLC cell lines; and (6) in direct comparison, is more potent in vitro and more efficacious in vivo than ABT-263. To achieve the ultimate goal of developing BM-1197 as a new, effective, and personalized medicine for NSCLC, three specific aims will be pursued: 1) determine the antitumor activity of BM-1197 as a single agent in NSCLC in vitro and in vivo and identify the molecular determinants for its sensitivity; 2) determine the mechanism of action, antitumor activity, and potential toxicity of BM-1197-docetaxel combination in NSCLC in vitro and in vivo; and 3) determine the mechanism of action, antitumor activity, and potential toxicity of BM-1197-trametinib combination in NSCLC in vitro and in vivo. Multiple complementary preclinical models, including a large panel of well-characterized NSCLC cell lines, cell lined-derived xenografts, and patient-derived xenografts of NSCLC in mice will be employed. This project is expected to establish the strong antitumor activity of BM-1197 in complementary preclinical models of NSCLC and identify key molecular determinants for the sensitivity of BM- 1197 in the settings of single agent and combinations. BM-1197 is undergoing IND-enabling studies and will enter clinical trials shortly. Therefore, the success of this project will have a significant impact for translation of BM-1197 into a new therapy for NSCLC. Identifying the molecular determinants for the sensitivity of BM-1197 will greatly facilitate the development of BM-1197 as a novel personalized therapy for NSCLC.