化学
体内
咔唑
激酶
谱系(遗传)
结构-活动关系
体外
转移酶
立体化学
生物化学
分子生物学
酶
生物
基因
遗传学
有机化学
作者
Robert L. Hudkins,James L. Diebold,Ming Tao,Kurt A. Josef,Chung Ho Park,Thelma S. Angeles,Lisa D. Aimone,Jean Husten,Mark A. Ator,Sheryl L. Meyer,Beverly P. Holskin,John T. Durkin,А.А. Федоров,E.V. Fedorov,Steven C. Almo,Joanne R. Mathiasen,Donna Bozyczko‐Coyne,Michael S. Saporito,Richard Scott,John P. Mallamo
摘要
The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.
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