|
|
|
|
structure-based design of 6-chloro-4-aminoquinazoline-2-carboxamide derivatives as potent and selective p21-activated kinase 4 (pak4) inhibitors
|
|
|
|
|
|
|
|
نویسنده
|
hao c. ,zhao f. ,song h. ,guo j. ,li x. ,jiang x. ,huan r. ,song s. ,zhang q. ,wang r. ,wang k. ,pang y. ,liu t. ,lu t. ,huang w. ,wang j. ,lin b. ,he z. ,li h. ,li f. ,zhao d. ,cheng m.
|
|
منبع
|
journal of medicinal chemistry - 2018 - دوره : 61 - شماره : 1 - صفحه:265 -285
|
|
چکیده
|
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.
|
|
|
|
|
آدرس
|
shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, tsinghua university, tsinghua-peking joint center for life sciences, beijing advanced innovation center for structural biology, school of medicine, department of basic medical sciences, china, agency for science, technology and research, institute of materials research and engineering, singapore, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of public health, china medical university, department of cell biology, key laboratory of cell biology, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of public health, china medical university, key laboratory of medical cell biology, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of public health, china medical university, key laboratory of medical cell biology, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, shenyang pharmaceutical university, school of pharmacy, china, tsinghua university, school of medicine, tsinghua-peking joint center for life sciences, department of basic medical sciences, china, ministry of public health, china medical university, department of cell biology, key laboratory of cell biology, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china, ministry of education, shenyang pharmaceutical university, key laboratory of structure-based drug design and discovery, china
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Authors
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|