2023年首创性小分子药物研究实例浅析

First-in-class small molecule drugs in 2023

2023年是药物研发稳中求进的一年,小分子药物与生物药物的研发增长齐头并进。美国FDA药物评价和研究中心(CDER)在过去一年里共计批准了55款新药,相比2022年的37款新药获批数量提升明显,其中包括38款新分子实体、17款生物药物、5款基因疗法和2款细胞疗法。首创性(first-in-class)药物占比稳步增加,本年度获批13款小分子首创药物和7款生物首创药物,多数集中于肿瘤和罕见病领域。其中,多个首创性小分子药物具有突破性意义,例如首个神经激肽3(NK3)受体拮抗剂非唑奈坦(fezolinetant)、首个视黄酸受体(RIG-I)激动剂帕拉罗汀(palovarotene)、首个蛋白激酶B(AKT)抑制剂卡匹色替(capivasertib)、首个补体因子B抑制剂伊普可泮(iptacopan)等。首创性药物具有巨大的学术价值和商业价值,已成为当前学术界和工业界争相追寻的目标。然而,首创性药物不仅需要新靶标、新机制和新分子,更需要全面验证新靶标与疾病的因果性,研究新机制与药效之间的关联性,探索新分子与成药性之间的平衡关系,研发风险极大。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。

In 2023,drug discovery develops steadily,with improvement of small molecule drugs discovery keeps pace with biological drugs in this year.The Center for Drug Evaluation and Research of U.S.Food and Drug Administration has totally approved 55 kinds of new drugs which have significantly promotion compared to 37 new drugs approval in 2022,including 38 kinds of new molecular entities,17 kinds of biological drugs,5 kinds of gene therapeutics and 2 cell therapeutics.The proportion of first-in-class drugs increased steadily,with 13 small molecule first-in-class drugs and 7 biological first-in-class drugs approved this year,mostly in the fields of cancer and rare diseases.Among them,a plurality of first-initiated small molecule drugs exhibits breakthrough significance,such as the first neurokinin 3(NK3)receptor antagonist fezolinetant,the first retinoic acid receptor(RIG-I)agonist palovarotene,the first protein kinase B(AKT)inhibitor capivasertib,the first complement factor B inhibitor iptacopan,etc.The pioneering drug has huge academic and commercial value,and has become the target of the academic and industrial circles.However,first-in-class drugs not only need new targets,new mechanisms and new molecules,but also need to comprehensively verify the causality between new targets and diseases,study the correlation between new mechanisms and drug efficacy,and explore the balance between new molecules and drugmanufacturing properties.This article analyzed the research background,development process and therapeutic application of three first-initiated small molecule drugs in this year,expecting to provide more research ideas and methods for more first-in-class drugs.