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

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Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-06-14 , 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 ₆ , Bing Xiong ₁₀

Affiliation

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.
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.
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.
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.
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.
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.
Shenyang Pharmaceutical University, 103 Wenhua Rd, Shenyang, Liaoning, 110016, PR China.
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.
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.
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.

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 and , we designed and synthesized a series of pyrido[2,3-]pyrimidin-7(8)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure−activity relationship exploration was conducted. The representative compounds , and 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 phase. Inhibition mechanism study of compound indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 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.

中文翻译：

作为有效 USP1 抑制剂的吡啶并[2,3-d]嘧啶-7(8H)-酮衍生物的设计、合成和生物学评价

USP1 已成为单一治疗药物或与化疗和分子靶向治疗相结合的药物发现的新型潜在靶标。在本研究中，基于已公开的和的结构，我们通过环化策略和系统的构效关系探索，设计并合成了一系列吡啶并[2,3-]pyrimidin-7(8)-one衍生物作为有效的USP1抑制剂进行了。代表性化合物 , 并在 NCI-H1299 细胞中表现出优异的 USP1/UAF 抑制作用并表现出强大的抗增殖作用。进一步的流式细胞术分析表明，它们可以在此阶段阻止乳腺癌细胞 MDA-MB-436。化合物的抑制机制研究表明这些衍生物作为可逆且非竞争性的 USP1 抑制剂。值得注意的是，化合物与 PARP 抑制剂奥拉帕尼的组合在奥拉帕尼耐药的 MDA-MB-436/OP 细胞中产生了增强的细胞杀伤作用，并且化合物在小鼠中表现出优异的口服药代动力学特性。总的来说，我们的努力可能为开发新型 USP1 抑制剂作为单一治疗剂以及与 PARP 抑制剂联合使用提供可靠的基础。

更新日期：2024-06-14

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