Targeting apoptosis via chemical design of Bcl-2 antagonists

描述(由申请人提供)：大多数肺癌细胞的特征是抗凋亡的Bcl-2家族蛋白水平升高，由此导致的细胞死亡抑制会影响肿瘤的致瘤性、转移行为、化疗耐药性和放射耐药性。在非小细胞肺癌(NSCLC)中，抗凋亡的Bcl2蛋白，如Bclxl、Bcl2和Mcl-1的上调往往与对传统化疗和放疗的耐药有关，而传统的化疗和放疗是依赖于诱导细胞凋亡的治疗策略。因此，治疗癌症的新的优化策略可能会将传统的化疗药物与中和抗细胞凋亡的Bcl-2蛋白的分子结合起来。目前，针对Bcl-2的反义寡核苷酸(GenasenseTM)已处于治疗黑色素瘤和慢性淋巴细胞白血病(CLL)的第三阶段临床试验，这是由程序性缺陷细胞死亡和Bcl-xL/2过度表达引起的人类恶性肿瘤的典型例子。同样，一种双重的Bclxl/Bcl2小分子抑制剂(ABT-263，Abbott)正在推进对CLL患者的临床评估。然而，一些研究表明，在非小细胞肺癌(NSCLC)中，除了Bcl2和Bclxl外，Mcl-1的过度表达还决定了对化疗和放射的抵抗。因此，我们建议使用高度集成的多学科方法，包括创新的基于结构的设计、药物化学、基于细胞的和体内研究，以获得新的、有效的和类似药物的、主要针对Mcl-1、Bcl2和Bclxl的PAN-Bcl-2拮抗剂，重点是它们对非小细胞肺癌的开发。考虑到所提出的各种技术和替代方法，我们预计我们将能够找到诱导肺癌细胞凋亡的新型PAN-Bcl2拮抗剂，这些药物对目前的先进化合物如ABT-263或Genasense具有耐药性。 公共卫生相关性：包括Mcl-1蛋白在内的细胞凋亡调控基因表达的改变可能导致非小细胞肺癌(NSCLC)的发生，并对肿瘤对化疗和放射治疗的反应产生不利影响。因此，直接靶向Mcl-1的药物可以诱导肺癌细胞的凋亡，并使细胞对细胞毒药物诱导的细胞凋亡敏感。小分子Mcl-1抑制剂的开发为开发更有效的治疗非小细胞肺癌的联合疗法提供了一条有希望的途径。

DESCRIPTION (provided by applicant): Most lung cancer cells are characterized by elevated levels of anti-apoptotic Bcl-2 family proteins and the resulting inhibition of cell-death influences tumorigenicity, metastatic behavior, chemoresistance and radioresistance. In non-small-cell lung cancer (NSCLC) upregulation of anti-apoptotic Bcl-2 proteins, such as Bcl-xL, Bcl-2 and Mcl-1, is often associated with resistance to traditional chemotherapy and radiation, which are therapeutic strategies that rely on the ability to induce apoptosis. Thus, novel optimized strategies for treatment of cancer might combine traditional chemotherapeutics with molecules that neutralize the effects of the anti-apoptotic Bcl-2 proteins. Already, Bcl-2- targeting antisense oligonucleotides (GenasenseTM) are in Phase III clinical trials for melanoma and chronic lymphocytic leukemia (CLL), a quintessential example of a human malignancy caused by defective programmed cell death and Bcl-xL/2 over- expression. Similarly, a dual Bcl-xL/Bcl-2 small molecule inhibitor (ABT-263, Abbott) is advancing clinical evaluation for patients affected by CLL. However, several studies suggest that in non-small cell lung cancers (NSCLC), in addition to Bcl-2 and Bcl-xL, Mcl-1 over-expression dictates resistance to chemotherapy and radiation. Hence, we propose to use a highly integrated multidisciplinary approach involving innovative structure-based design, medicinal chemistry, cell-based and in vivo studies to derive novel, potent and drug-like pan-Bcl-2 antagonists that primarily target Mcl-1, Bcl2 and Bcl-xL, focusing on their development against NSCLC. Given the arsenal of techniques and alternative approaches proposed, we anticipate that we will be able to identify novel pan-Bcl-2 antagonists that induce apoptosis in lung cancer cells that are resistant to current advanced compounds such as ABT-263 or Genasense. PUBLIC HEALTH RELEVANCE: Alterations in the expression of the apoptosis-regulating Bcl-2 genes, including the protein Mcl-1, can contribute to the origins of non-small cell lung cancers (NSCLC), as well as adversely influence tumor responses to chemo- and radiotherapy. Therefore, agents that directly target Mcl-1 can induce apoptosis and sensitize cells to apoptosis induced by cytotoxic agents in lung cancer. The development of small molecule Mcl-1 inhibitors represent a promising route for the development of more effective combination therapies for the treatment of NSCLC.