Szczepankiewicz, BG; Kosogof, C; Nelson, LTJ; Liu, G; Liu, B; Zhao, HY; Serby, MD; Xin, ZL; Liu, M; Gum, RJ; Haasch, DL; Wang, SY; Clampit, JE; Johnson, EF; Lubben, TH; Stashko, MA; Olejniczak, ET; Sun, CH; Dorwin, SA; Haskins, K; Abad-Zapatero, C; Fry, EH; Hutchins, CW; Sham, HL; Rondinone, CM; Trevillyan, JM
The c-Jun N-terminal kinases ( JNK-1, -2, and -3) are members of the mitogen activated protein ( MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38 alpha, and p38 delta and showed little inhibitory activity against a panel of 74 kinases.