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Bcl-2家族蛋白水平升高，由此产生的细胞死亡抑制影响致瘤性、转移行为、化学耐药和放射耐药。在非小细胞肺癌（NSCLC）中，抗凋亡Bcl-2蛋白（如Bcl-xL、Bcl-2和Mcl-1）的上调通常与对传统化疗和放疗的耐药性有关，而传统化疗和放疗是依赖于诱导凋亡能力的治疗策略。因此，新的优化癌症治疗策略可能将传统化疗药物与中和抗凋亡Bcl-2蛋白作用的分子结合起来。目前，针对Bcl-2的反义寡核苷酸（GenasenseTM）已进入治疗黑色素瘤和慢性淋巴细胞白血病（CLL）的III期临床试验，后者是由缺陷性程序性细胞死亡和Bcl-xL/2过表达引起的人类恶性肿瘤的典型例子。类似地，双重Bcl-xL/Bcl-2小分子抑制剂（ABT-263，雅培）正在推进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Bcl-2和Bcl-xL外，Mcl-1的过表达决定了对化疗和放疗的耐药性。因此，我们建议采用高度整合的多学科方法，包括创新的基于结构的设计、药物化学、基于细胞和体内的研究，以获得主要针对Mcl-1、Bcl2和Bcl-xL的新型、有效和药物样的泛bcl -2拮抗剂，重点研究它们针对非小细胞肺癌的开发。鉴于所提出的技术和替代方法，我们预计我们将能够鉴定出新的pan-Bcl-2拮抗剂，这些拮抗剂可诱导对ABT-263或Genasense等当前先进化合物耐药的肺癌细胞凋亡。

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.