2. Academic Validation
  3. Discovery of the Clinical Candidate YY2201 as a Highly Potent and Selective ATR Inhibitor

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

  • J Med Chem. 2025 Mar 13;68(5):5292-5311. doi: 10.1021/acs.jmedchem.4c02380.
Meng Wu 1,  Xiaofang Chen 2,  Haoran Wang 3,  Chang Li 4,  Wenjin Liu 5,  Xiao Zheng 2,  Jingxin Yang 3,  Xin Ye 6,  Yali Weng 7,  Tianyun Fan 2,  Huimin Hou 3
Affiliations

Affiliations

  • 1 Center for Drug Research and Evaluation, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P. R. China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. China.
  • 3 Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P. R. China.
  • 4 Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P. R. China.
  • 5 Jiangsu YaYao Biotechnology Co., Ltd, Nanjing 210032, P. R. China.
  • 6 Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P. R. China.
  • 7 Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P. R. China.
PMID: 40029060 DOI: 10.1021/acs.jmedchem.4c02380
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-172448
    ATR Inhibitor