Zhang Mingzhen, Jang Hyunbum, Nussinov Ruth
Computational Structural Biology Section , Frederick National Laboratory for Cancer Research , National Cancer Institute at Frederick , Frederick , MD 21702 , USA . Email:
Department of Human Molecular Genetics and Biochemistry , Sackler School of Medicine , Tel Aviv University , Tel Aviv 69978 , Israel.
Chem Sci. 2020 May 19;11(23):5855-5865. doi: 10.1039/d0sc01676d. eCollection 2020 Jun 21.
The search is on for effective specific inhibitors for PI3Kα mutants. PI3Kα, a critical lipid kinase, has two subunits, catalytic and inhibitory. PIK3CA, the gene that encodes the p110α catalytic subunit is a highly mutated protein in cancer. Dysregulation of PI3Kα signalling is commonly associated with tumorigenesis and drug resistance. Despite its vast importance, only recently the FDA approved the first drug (alpelisib by Novartis) for breast cancer. A second (GDC0077), classified as PI3Kα isoform-specific, is undergoing clinical trials. Not surprisingly, these ATP-competitive drugs commonly elicit severe concentration-dependent side effects. Here we briefly review PI3Kα mutations, focus on PI3K drug repertoire and propose new, to-date unexplored PI3Kα therapeutic strategies. These include (1) an allosteric and orthosteric inhibitor combination and (2) taking advantage of allosteric rescue mutations to guide drug discovery.
人们正在寻找针对PI3Kα突变体的有效特异性抑制剂。PI3Kα是一种关键的脂质激酶，有催化和抑制两个亚基。编码p110α催化亚基的基因PIK3CA在癌症中是一种高度突变的蛋白。PI3Kα信号失调通常与肿瘤发生和耐药性相关。尽管其极为重要，但直到最近美国食品药品监督管理局才批准了第一种用于乳腺癌的药物（诺华公司的阿培利司）。第二种药物（GDC0077），被归类为PI3Kα亚型特异性药物，正在进行临床试验。不出所料，这些ATP竞争性药物通常会引发严重的浓度依赖性副作用。在此，我们简要回顾PI3Kα突变，聚焦于PI3K药物种类，并提出新的、迄今尚未探索的PI3Kα治疗策略。这些策略包括：（1）变构抑制剂与正构抑制剂联合使用；（2）利用变构拯救突变来指导药物研发。
