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Rational Design of PARP1/c-Met Dual Inhibitors for Overcoming PARP1 Inhibitor Resistance Induced by c-Met Overexpression.
Sun, Zeren; Li, Lanjie; Zhai, Bingxin; Hu, Mengxuan; Huang, Lei; Huang, Shihui; Ye, Liu; Kong, Xiangying; Xu, Jie; Bai, Jie; Yan, Jingjie; Zhou, Qichen; Hu, Zheqi; Zhang, Yuchen; Jiang, Yuhan; Zhang, Yan; Qiao, Zhou; Zou, Yi; Xu, Yungen; Zhu, Qihua.
Afiliación
  • Sun Z; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Li L; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Zhai B; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Hu M; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Huang L; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Huang S; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Ye L; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Kong X; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Xu J; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Bai J; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • Yan J; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • Zhou Q; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Hu Z; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Zhang Y; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Jiang Y; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • Zhang Y; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • Qiao Z; China Pharmaceutical University Center for Analysis and Testing, China Pharmaceutical University, Nanjing 211198, China.
  • Zou Y; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • Xu Y; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • Zhu Q; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
J Med Chem ; 67(6): 4916-4935, 2024 Mar 28.
Article en En | MEDLINE | ID: mdl-38477575
ABSTRACT
The emergence of resistance to PARP1 inhibitors poses a current therapeutic challenge, necessitating the development of novel strategies to overcome this obstacle. The present study describes the design and synthesis of a series of small molecules that target both PARP1 and c-Met. Among them, compound 16 is identified as a highly potent dual inhibitor, exhibiting excellent inhibitory activities against PARP1 (IC50 = 3.3 nM) and c-Met (IC50 = 32.2 nM), as well as demonstrating good antiproliferative effects on HR-proficient cancer cell lines and those resistant to PARP1 inhibitors. Importantly, compound 16 demonstrates superior antitumor potency compared to the PARP1 inhibitor Olaparib and the c-Met inhibitor Crizotinib, either alone or in combination, in MDA-MB-231 and HCT116OR xenograft models. These findings highlight the potential of PARP1/c-Met dual inhibitors for expanding the indications of PARP1 inhibitors and overcoming tumor cells' resistance to them.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Poli(ADP-Ribosa) Polimerasas / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Poli(ADP-Ribosa) Polimerasas / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos