Chemical Inhibitors of Anti-Apoptotic Bcl-2 Family Proteins

抗细胞凋亡的Bcl2家族蛋白的化学抑制剂 Bcl2(B细胞淋巴细胞/白血病2)家族的蛋白质是内源性细胞凋亡途径的重要组成部分。 几个同源物，如通过与Bcl2中的四个BH同源(BH)结构域的部分或全部序列相似性所定义的， 在人类中发现，并具有抗或促凋亡功能。抗凋亡的Bcl-2蛋白的上调通常是 与多种癌症的发生和发展有关。此外，过表达Bcl-2的癌细胞 耐受传统的化疗和放射治疗策略，依赖于诱导细胞凋亡的能力。 因此，治疗癌症的新的优化策略可能基于中和药物影响的分子。 抗细胞凋亡的Bcl2蛋白。事实上，以bcl2为靶点的反义寡核苷酸(Genasense)正处于第三阶段临床 慢性淋巴细胞白血病、骨髓瘤和黑色素瘤的治疗试验及小鼠体内研究 人类淋巴瘤模型已经证明了它们的有效性。然而，一种靶向Bcl-2的小分子药物方法 从成本和传递便利性的角度来看，蛋白质将是更可取的。另外，考虑到其他抗凋亡剂 Bcl2家族的成员，如Bclxl和Mcl-1，可以在细胞凋亡抑制中发挥重要作用 不同的癌细胞，同时靶向几个抗凋亡的Bcl-2家族蛋白的化合物可能是 为了达到最佳的疗效，抑制Bcl-2家族蛋白的抗凋亡作用的一种策略是 模拟促凋亡性BH3的化合物阻断它们与促凋亡性Bcl-2家族成员的相互作用 域名。在这方面，我们最近发现，某些具有抗癌活性的天然产品 在体外和细胞内均能通过这一机制直接抑制Bcl2和Bclxl。在本申请中，我们建议 使用现代生物物理技术、基于结构的设计和药物化学的组合来设计和 合成新的、优化的化合物，提高药物的相似性、效力和选择性。我们的最终目标是 产生新的化学实体，显示出强大的基于机制的抗细胞凋亡活性 蛋白质，将这些化合物推进到体外基于细胞的和体内的肿瘤移植模型中，因此提供了一种 为癌症治疗设计新疗法的坚实平台。

Chemical inhibitors of anti-apoptotic Bcl-2-family proteins Proteins in the Bcl-2 (B-cell lymphocyte/leukemia-2) family are critical components of the intrinsic apoptotic pathway. Several homologs, as defined by sequence similarity to some or all of the four Bcl-2 homology (BH) domains in Bcl-2, are found in humans and have anti- or pro-apoptotic function. Up-regulation of anti-apoptotic Bcl-2 proteins is often associated with the onset and progression of many type of cancer. Moreover, Bcl-2 over-expressing cancer cells are resistant to traditional, chemotherapy and radiation, therapeutic strategies that rely on the ability to induce apoptosis. Thus, novel optimized strategies for treatment of cancer might be based on molecules that neutralize the effects of the anti-apoptotic Bcl-2 proteins. In fact, Bcl-2-targeting antisense oligonucleotides (Genasense) are in Phase III clinical trials for the treatment of chronic lymphocytic leukemia, myeloma, and melanoma and in vivo studies with mouse models of human lymphomas have proven their efficacy. However, a small-molecule drug approach to targeting Bcl-2 proteins would be preferable from the standpoint of cost and convenience of delivery. Also, given that other antiapoptotic members of the Bcl-2 family, such as Bcl-xL and Mcl-1, can play important roles in apoptosis-suppression in different cancer cells, compounds that simultaneously target several anti-apoptotic Bcl-2-family proteins may be required for optimal efficacy, One strategy to suppress the anti-apoptotic effect of Bcl-2 family proteins is the disruption of their interaction with pro-apoptotic Bcl-2 family members by compounds that mimic pro-apoptotic BH3 domains. In this regard, we-have recently discovered that certain natural products with demonstrated anticancer activity are able to directly inhibit Bcl-2 and Bcl-xL in vitro and in cell via this mechanism. In this application, we propose to use a combination of modern biophysical techniques, structure-based design, and medicinal chemistry to design and synthesize novel, optimized compounds with increased drug-likeness, potency and selectivity. Our final goal is to generate novel chemical entities that demonstrate potent mechanism-based activity against anti-apoptotic Bcl-2 proteins, advancing these compounds into in vitro cell-based and in vivo tumor xenograft models, therefore providing a solid platform towards the design of novel therapies for the treatment of cancer.