Targeting Protein Kinase, Membrane-Associated Tyrosine/Threonine 1 (PKMYT1) for Precision Cancer Therapy: From Discovery to Clinical Trial

Abstract

\Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1), an overlooked member of the WEE family responsible for regulating cell cycle transition, has recently emerged as a compelling therapeutic target for precision cancer therapy due to its established synthetic lethal relationship with CCNE1 (cyclin E1) amplification. Since the first-in-class selective PKMYT1 inhibitor, RP-6306, entered clinical trials in 2021, the field has experienced renewed interest underscored by the growing number of inhibitor patents and the exploration of additional gene alterations, such as KRAS/p53 mutations, FBXW7 mutation, and PPP2R1A mutation, as novel synthetic lethal partners. This perspective summarizes, for the first time, the PKMYT1 structure, function, and inhibitors in both the literature and patent applications reported to date. Compounds are described focusing on their design and optimization process, structural features, and biological activity with the aim to promoting further drug discovery efforts targeting PKMYT1 as a potential precision therapy. ■ SIGNIFICANCEThis perspective presents, for the first time, an overview of the structure, function, and inhibitor development of PKMYT1 in both the literature and patent applications. Compounds are described emphasizing design concepts and structure−activity relationships (SAR), which delineate potential avenues for development of more potent and selective PKMYT1 inhibitors for precision cancer therapy.