化学
激酶
蛋白激酶A
威罗菲尼
肝再生
生物化学
体内
细胞生物学
再生(生物学)
癌症研究
生物
遗传学
黑色素瘤
转移性黑色素瘤
作者
Bent Pfaffenrot,Philip Klövekorn,Michael Juchum,Roland Selig,Wolfgang Albrecht,Lars Zender,Stefan Laufer
标识
DOI:10.1016/j.ejmech.2021.113371
摘要
Currently, the therapeutic options for treatment of liver failure are very limited. As mitogen-activated protein kinase kinase 4 (MKK4) has recently been identified by in vivo RNAi experiments to be a major regulator in hepatocyte regeneration, we pursued the development of a small molecule targeting this protein kinase. Starting from the approved BRAFV600E inhibitor vemurafenib (8), that showed a high off-target affinity to MKK4 in an initial screening, we followed a scaffold-hopping approach, changing the core heterocycle from 1H-pyrrolo[2,3-b]pyridine to 1H-pyrazolo[2,3-b]pyridine (10). Affinity to MKK4 could be conserved while the selectivity against off-target protein kinases was slightly improved. Further modifications led to 58 and 59 showing high affinity to MKK4 in the low nanomolar range and excellent selectivity profile from mandatory multiparameter-optimization for the essential anti-targets (MKK7, JNK1) and off-targets (BRAF, MAP4K5, ZAK) in the MKK4 pathway. Herein we report the first selective MKK4 inhibitors in this class.
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