2. Academic Validation
  3. Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors

Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors

  • Eur J Med Chem. 2024 Jun 14:275:116568. doi: 10.1016/j.ejmech.2024.116568.
Hongrui Li 1,  Ben-Jin Liu 2,  Jiahao Xu 3,  Shan-Shan Song 4,  Ruixian Ba 1,  Junjie Zhang 5,  Xia-Juan Huan 6,  Dun Wang 7,  Ze-Hong Miao 8,  Tongchao Liu 9,  Jin-Xue He 10,  Bing Xiong 11
Affiliations

Affiliations

  • 1 Shenyang Pharmaceutical University, 103 Wenhua Rd, Shenyang, Liaoning, 110016, PR China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, PR China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Yangtze Delta Drug Advanced Research Institute, 100 Dongtinghu Road, Nantong, 226133, PR China.
  • 2 School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, PR China; State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, PR China.
  • 3 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, PR China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Yangtze Delta Drug Advanced Research Institute, 100 Dongtinghu Road, Nantong, 226133, PR China; School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, PR China.
  • 4 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, PR China.
  • 5 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, PR China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of the Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, PR China.
  • 6 University of the Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, PR China; State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, PR China.
  • 7 Shenyang Pharmaceutical University, 103 Wenhua Rd, Shenyang, Liaoning, 110016, PR China.
  • 8 School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, PR China; University of the Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, PR China; State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, PR China.
  • 9 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, PR China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: tongchao_liu@simm.ac.cn.
  • 10 University of the Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, PR China; State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, PR China. Electronic address: jinxue_he@simm.ac.cn.
  • 11 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, PR China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of the Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, PR China; Yangtze Delta Drug Advanced Research Institute, 100 Dongtinghu Road, Nantong, 226133, PR China. Electronic address: bxiong@simm.ac.cn.
PMID: 38889606 DOI: 10.1016/j.ejmech.2024.116568
Abstract

USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI-H1299 cells. Further flow cytometry analysis revealed that they could arrest breast Cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP Inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 Inhibitor as a single therapeutic agent and in combination with PARP inhibitors.

Keywords

Olaparib-resistant cell; Structure-activity relationships; USP1 inhibitor.

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