Centre for Biomolecular Sciences , University Park Nottingham , Nottingham NG7 2RD , U.K.
J Med Chem. 2019 May 23;62(10):4815-4850. doi: 10.1021/acs.jmedchem.8b01492. Epub 2018 Dec 24.
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH of the inositol ring of phosphoinositides, and deregulation of this pathway has implications in many diseases. The search for novel PI3K inhibitors has been at the forefront of academic and industrial medicinal chemistry with over 600 medicinal chemistry-based publications and patents appearing to date, leading to 38 clinical candidates and the launch of two drugs, idelalisib in 2014 and copanlisib in 2017. This Perspective will discuss medicinal chemistry design approaches to novel isoform-selective inhibitors through consideration of brief case histories of compounds that have progressed into clinical development or that have revealed new structural motifs in this highly competitive area of research.
磷脂酰肌醇 3-激酶（PI3Ks）是一类脂质激酶，可磷酸化磷脂酰肌醇中肌醇环的 3-OH 位，该途径的失调与许多疾病有关。寻找新型 PI3K 抑制剂一直是学术和工业药物化学的前沿领域，迄今为止已有超过 600 篇基于药物化学的出版物和专利，由此产生了 38 个临床候选药物，并推出了两种药物，即 2014 年的idelalisib 和 2017 年的copanlisib。本文将通过简要回顾已进入临床开发或在这一极具竞争力的研究领域中揭示新结构基序的化合物的案例史，讨论新型同工型选择性抑制剂的药物化学设计方法。
