Discovery of the Clinical Candidate YY2201 as a Highly Potent and Selective ATR Inhibitor

• Published in: Journal of medicinal chemistry Vol. 68; no. 5; pp. 5292 - 5311
• Main Authors: Wu, Meng, Chen, Xiaofang, Wang, Haoran, Li, Chang, Liu, Wenjin, Zheng, Xiao, Yang, Jingxin, Ye, Xin, Weng, Yali, Fan, Tianyun, Hou, Huimin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.03.2025; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Line, Tumor; Chemistry, Medicinal; Drug Discovery; Female; Humans; Life Sciences & Biomedicine; Male; Mice; Mice, Nude; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Science & Technology; Structure-Activity Relationship; Xenograft Model Antitumor Assays; ATAXIA-TELANGIECTASIA; DNA-DAMAGE RESPONSE; OPTIMIZATION
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c02380

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.