Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
Clin Cancer Res. 2015 Jun 15;21(12):2671-6. doi: 10.1158/1078-0432.CCR-14-0959. Epub 2015 Apr 2.
The inhibition of apoptosis enables the survival and proliferation of tumors and contributes to resistance to conventional chemotherapy agents and is therefore a very promising avenue for the development of new agents that will enhance current cancer therapies. The BCL-2 family proteins orchestrate apoptosis at the mitochondria and endoplasmic reticulum and are involved in other processes such as autophagy and unfolded protein response (UPR) that lead to different types of cell death. Over the past decade, significant efforts have been made to restore apoptosis using small molecules that modulate the activity of BCL-2 family proteins. The small molecule ABT-199, which antagonizes the activity of BCL-2, is currently the furthest in clinical trials and shows promising activity in many lymphoid malignancies as a single agent and in combination with conventional chemotherapy agents. Here, we discuss strategies to improve the specificity of pharmacologically modulating various antiapoptotic BCL-2 family proteins, review additional BCL-2 family protein interactions that can be exploited for the improvement of conventional anticancer therapies, and highlight important points of consideration for assessing the activity of small-molecule BCL-2 family protein modulators.
细胞凋亡的抑制使肿瘤能够存活和增殖，并有助于抵抗传统的化疗药物，因此，开发新的药物以增强当前的癌症治疗方法是非常有前途的途径。BCL-2 家族蛋白在线粒体和内质网中调控细胞凋亡，并参与其他过程，如自噬和未折叠蛋白反应 (UPR)，导致不同类型的细胞死亡。在过去的十年中，人们做出了巨大的努力，使用能够调节 BCL-2 家族蛋白活性的小分子来恢复细胞凋亡。小分子 ABT-199 拮抗 BCL-2 的活性，目前在临床试验中进展最快，作为单一药物和与传统化疗药物联合使用时，在许多淋巴恶性肿瘤中显示出有希望的活性。在这里，我们讨论了提高药理调节各种抗凋亡 BCL-2 家族蛋白特异性的策略，回顾了可用于改善传统抗癌治疗的其他 BCL-2 家族蛋白相互作用，并强调了评估小分子 BCL-2 家族蛋白调节剂活性的重要考虑因素。
