Discovery of the Clinical Candidate <b>YY2201</b> as a Highly Potent and Selective ATR Inhibitor

ATR is one of the key DNA damage response (DDR) regulatory factors to maintain genome stability. ATR inhibition induces DNA damage accumulation and apoptosis in DDR kinase mutation or deficiency cancer cells through synthetic lethality, making it a promising target for treatment of cancers with DDR defects. Herein, we describe the discovery and preclinical evaluation of YY2201, a highly potent and selective novel ATR inhibitor, with favorable ADME, safety pharmacology, and pharmacokinetics profiles. YY2201 efficiently inhibits tumor progression in broad-spectrum cancer types, both in vitro and in vivo. YY2201 shows superior in vivo anticancer efficacy and a better therapeutic index compared to AZD6738 in a lung cancer xenograft model. YY2201 also exhibits potent cancer suppression effects in combination with chemotherapy in vivo. Currently, the investigational new drug application of YY2201 has been approved by the FDA for further clinical investigation.ATR（共济失调毛细血管扩张症和Rad3相关蛋白，Ataxia Telangiectasia and Rad3-related）是维持基因组稳定性的关键DNA损伤应答（DNA Damage Response, DDR）调控因子之一。ATR抑制可通过合成致死效应，在DDR激酶突变或缺陷的癌细胞中诱导DNA损伤积累与细胞凋亡，使其成为DDR缺陷型癌症治疗的极具潜力的靶点。本文报道了YY2201的发现及临床前评价结果：YY2201是一种强效、高选择性的新型ATR抑制剂，具备优良的ADME（吸收、分布、代谢、排泄）特性、安全药理学及药代动力学特征。YY2201可在体外及体内有效抑制广谱癌症类型的肿瘤进展；在肺癌异种移植模型中，其相较于AZD6738展现出更优异的体内抗肿瘤活性与更佳的治疗指数。此外，YY2201与化疗联合使用时，在体内可展现出强效的肿瘤抑制效果。目前，YY2201的研究性新药申请已获美国食品药品监督管理局（FDA）批准，将开展进一步的临床研究。