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在于抗凋亡Bcl-2家族蛋白水平升高，并且由此产生的细胞死亡抑制影响致瘤性、转移行为、化学抗性和放射抗性。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抗性相关，这些化疗和放疗是依赖于诱导凋亡能力的治疗策略。因此，用于治疗癌症的新的优化策略可以将联合收割机传统的化学治疗剂与中和抗凋亡Bcl-2蛋白的作用的分子结合。Bcl-2靶向反义寡核苷酸（GenasenseTM）已经在黑色素瘤和慢性淋巴细胞白血病（CLL）的III期临床试验中，慢性淋巴细胞白血病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，Abbott）正在推进对受CLL影响的患者的临床评价。然而，一些研究表明，在非小细胞肺癌（NSCLC）中，除了Bcl-2和Bcl-xL，Mcl-1过表达决定了对化疗和放疗的抗性。因此，我们建议使用一个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，基于细胞和体内研究，以获得新的，有效的和药物样的泛Bcl-2拮抗剂，主要针对Mcl-1，Bcl-2和Bcl-xL，专注于他们对NSCLC的发展。考虑到所提出的技术和替代方法的库，我们预计我们将能够识别新的泛Bcl-2拮抗剂，其在对当前先进化合物（如ABT-263或Genasense）具有抗性的肺癌细胞中诱导凋亡。

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.