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
  • 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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