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Discovery of Highly Potent Small-Molecule PD-1/PD-L1 Inhibitors with a Novel Scaffold for Cancer Immunotherapy.
Xu, Yongling; Du, Huijie; Guo, Weibo; Liu, Beibei; Yan, Wenxin; Zhang, Chi; Qin, Long; Huang, Jingling; Wang, Hongxia; Wu, Shiqi; Ren, Weijie; Zou, Yi; Wang, Jie; Zhu, Qihua; Xu, Yungen; Gu, Hongfeng.
Afiliación
  • Xu Y; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Du H; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Guo W; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Liu B; Xi'an Xintong Pharmaceutical Research Co., Ltd, Xi'an 710061, China.
  • Yan W; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Zhang C; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Qin L; Xi'an Xintong Pharmaceutical Research Co., Ltd, Xi'an 710061, China.
  • Huang J; Xi'an Xintong Pharmaceutical Research Co., Ltd, Xi'an 710061, China.
  • Wang H; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Wu S; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Ren W; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Zou Y; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Wang J; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Zhu Q; China Pharmaceutical University Center for Analysis and Testing, China Pharmaceutical University, Nanjing 211198, China.
  • Xu Y; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • Gu H; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
J Med Chem ; 67(5): 4083-4099, 2024 Mar 14.
Article en En | MEDLINE | ID: mdl-38348878
ABSTRACT
Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in cancer immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Puntos de Control Inmunológico / Neoplasias Límite: Animals / 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
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Puntos de Control Inmunológico / Neoplasias Límite: Animals / 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