2022年首创性小分子药物研究实例浅析

First-in-class small molecule drugs in 2022

2022年,是全球经历新冠疫情侵扰的第三个年头,其对药物研发的影响也逐渐显现。美国FDA药物评价和研究中心(CDER)在过去一年里共计批准了37款新药,相比2021年50款新药获批的历史峰值有了明显下降。首创性(first-in-class)药物仍是新药获批的主力军,本年度共计有21款,其中小分子的首创性药物有7款。今年新药获批的总数虽大幅下降,但其中不乏多款具有重要借鉴意义的首创性小分子药物,例如首款口服丙酮酸激酶(PK)激活剂米他匹伐(mitapivat),首个选择性心肌β肌球蛋白三磷酸腺苷(ATP)酶变构抑制剂玛伐凯泰(mavacamten),首个靶向TYK2(酪氨酸激酶2)的氘代变构抑制剂氘可来昔替尼(deucravacitinib),首个靶向HIV衣壳的长效抑制剂来那帕韦(lenacapavir)等。首创性药物的研究需要聚焦临床难点问题,通过全新的作用靶标和生物机制实现对特定疾病的治疗效果。在生物机制研究、靶标选择、分子筛选、先导物确定、成药性优化等多方面研究过程中均存在巨大挑战,成功的首创性药物研发过程具有重要的学习和借鉴意义。本文通过浅析本年度3个首创性小分子药物的研发背景、研发过程和治疗应用,以期为更多的首创性药物提供研究思路与方法。

2022 is the third year of the global COVID-19 pandemic,and its troubles on new drug discovery are gradually apparent.37 new drugs were approved by the FDA's Center for Drug Evaluation and Research(CDER)last year,down from the peak of 50 new drug approvals in 2021.Notably,first-in-class drugs still occupy a dominant position this year,with a total of 21 drugs.Among them,7 are first-in-class small molecule drugs.Although the total number of new drug approvals in 2022 sharply decreased,some first-in-class small molecule drugs were regarded as significant,including mitapivat,the first oral activator targeting the pyruvate kinase(PK);mavacamten,the first selective allosteric inhibitor targeting the myocardialβmyosin ATPase;deucravacitinib,the first deuterated allosteric inhibitor targeting the tyrosine kinase 2(TYK2);and lenacapavir,the first long-acting inhibitor targeting the HIV capsid.Generally,the research of first-in-class drugs needs to focus on difficult clinical problems and can treat some specific diseases through novel targets and biological mechanisms.There are tremendous challenges in the research processes of new drugs,including biological mechanism research,target selection,molecular screening,lead compound identification and druggability optimization.Therefore,the success of first-in-class drugs development has prominent guidance significance for new drug discovery.This review briefly describes the discovery background,research and development process and therapeutic application of 3 firstin-class small molecule drugs to provide research ideas and methods for more first-in-class drugs.