2. Academic Validation
  3. Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors

  • J Med Chem. 2018 Jan 11;61(1):265-285. doi: 10.1021/acs.jmedchem.7b01342.
Chenzhou Hao 1,  Fan Zhao 2,  Hongyan Song 3,  Jing Guo 1,  Xiaodong Li 4,  Xiaolin Jiang 1,  Ran Huan 4,  Shuai Song 1,  Qiaoling Zhang 1,  Ruifeng Wang 1,  Kai Wang 1,  Yu Pang 1,  Tongchao Liu 1,  Tianqi Lu 4,  Wanxu Huang 1,  Jian Wang 1,  Bin Lin 1,  Zhonggui He 5,  Haitao Li 2,  Feng Li 4,  Dongmei Zhao 1,  Maosheng Cheng 1
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University , Shenyang 110016, China.
  • 2 Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University , Beijing 100084, China.
  • 3 Institute of Materials Research and Engineering, A*STAR (Agency for Science, Technology and Research) , 2 Fusionopolis Way, Innovis, #08-03, Singapore 138634.
  • 4 Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University , Shenyang 110001, China.
  • 5 School of Pharmacy, Shenyang Pharmaceutical University , Shenyang 110016, China.
PMID: 29190083 DOI: 10.1021/acs.jmedchem.7b01342
Abstract

Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2,4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors' selectivity, therapeutic potency, and pharmaceutical properties were optimized. One of the best compounds, 31 (CZh226), showed remarkable PAK4 selectivity (346-fold vs PAK1) and favorable kinase selectivity profile. Moreover, this compound potently inhibited the migration and invasion of A549 tumor cells by regulating the PAK4-directed downstream signaling pathways in vitro. Taken together, these data support the further development of 31 as a lead compound for PAK4-targeted Anticancer drug discovery and as a valuable research probe for the further biological investigation of group II PAKs.

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