Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes.
Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes.
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DOI：
10.1021/acs.jmedchem.0c02274
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发表时间：
2021-08-12
影响因子：
7.3
通讯作者：
Drewry DH
中科院分区：
文献类型：
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作者：
Eduful BJ;O'Byrne SN;Temme L;Asquith CRM;Liang Y;Picado A;Pilotte JR;Hossain MA;Wells CI;Zuercher WJ;Catta-Preta CMC;Zonzini Ramos P;Santiago AS;Couñago RM;Langendorf CG;Nay K;Oakhill JS;Pulliam TL;Lin C;Awad D;Willson TM;Frigo DE;Scott JW;Drewry DH
CAMKK2是一种丝氨酸/苏氨酸激酶，是AMPK的激活剂，其失调与多种疾病有关。不幸的是，通常用于探测CAMKK2信号的工具抑制剂STO-609具有局限性。为了确定有前景的支架作为开发高质量CAMKK2化学探针的起点，我们利用铰链结合的支架跳跃策略来设计新的CAMKK2抑制剂。从强效但混杂的双取代7-氮杂酚GSK650934开始，共合成了32个由单环、5,6-和6,6-融合杂芳香核心组成的化合物。该化合物集被专门设计用于探测与激酶铰链结合残基的相互作用。与GSK650394和STO-609相比，13种化合物在体外表现出相似或更好的CAMKK2抑制效力，而化合物13g和45在整个kinome中具有更好的CAMKK2选择性。我们对铰链结合的化学型进行了系统的调查，确定了几种有效的选择性CAMKK2抑制剂，作为药物化学计划的起点。
CAMKK2 is a serine/threonine kinase and an activator of AMPK whose dysregulation is linked with multiple diseases. Unfortunately, STO-609, the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations. To identify promising scaffolds as starting points for the development of high-quality CAMKK2 chemical probes, we utilized a hinge-binding scaffold hopping strategy to design new CAMKK2 inhibitors. Starting from the potent but promiscuous disubstituted 7-azaindole GSK650934, a total of 32 compounds, composed of single-ring, 5,6-, and 6,6-fused heteroaromatic cores, were synthesized. The compound set was specifically designed to probe interactions with the kinase hinge-binding residues. Compared to GSK650394 and STO-609, 13 compounds displayed similar or better CAMKK2 inhibitory potency in vitro, while compounds 13g and 45 had improved selectivity for CAMKK2 across the kinome. Our systematic survey of hinge-binding chemotypes identified several potent and selective inhibitors of CAMKK2 to serve as starting points for medicinal chemistry programs.
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影响因子：
7.3
作者：
Beno, Brett R.;Yeung, Kap-Sun;Meanwell, Nicholas A.
通讯作者：
Meanwell, Nicholas A.
影响因子：
11.2
作者：
Frigo DE;Howe MK;Wittmann BM;Brunner AM;Cushman I;Wang Q;Brown M;Means AR;McDonnell DP
通讯作者：
McDonnell DP
MicroRNA-224 及其靶标 CAMKK2 协同影响前列腺癌的肿瘤进展和患者预后
影响因子：
--
作者：
Fu, Hao;He, Hui-chan;Zhong, Wei-de
通讯作者：
Zhong, Wei-de
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
46.9
作者：
Davis, Mindy I.;Hunt, Jeremy P.;Zarrinkar, Patrick P.
通讯作者：
Zarrinkar, Patrick P.