Katzengruber Leon, Sander Pascal, Zwirner Stefan, Rasch Alexander, Eberlein Eric, Selig Roland, Albrecht Wolfgang, Zender Lars, Laufer Stefan A
Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, Germany.
Department of Chemical and Systems Biology, Stanford University, 290 Jane Stanford Way, Stanford, California 94305, United States.
J Med Chem. 2025 Jul 24;68(14):14782-14805. doi: 10.1021/acs.jmedchem.5c00919. Epub 2025 Jul 11.
Due to limited treatment options, liver failure remains a major challenge in modern medicine. With the validation of mitogen-activated protein kinase kinase 4 (MKK4, also known as MEK4 or MAP2K4) as a regulator of hepatocyte regeneration, a promising target for curative treatment of degenerative liver diseases was recently identified via in vivo RNAi experiments. The field of small molecules targeting MKK4 is of growing interest. Several MKK4 inhibitors with differing scaffolds are known, but few have reasonable selectivity profiles and drug-like properties. To further explore the space of drug-like MKK4 scaffolds, we performed a broad screening campaign and identified BI-D1870 as a promising candidate. The dihydropteridinone BI-D1870 is an unselective ribosomal S6 kinase inhibitor with broad off-target activity. In the study presented herein, we report a successful off-to-on target strategy that led to the development of highly selective 1,4-dihydropyrido[3,4-]pyrazin-3(2H)-one inhibitors of MKK4.
由于治疗选择有限，肝衰竭仍然是现代医学中的一项重大挑战。随着丝裂原活化蛋白激酶激酶4（MKK4，也称为MEK4或MAP2K4）作为肝细胞再生调节剂的验证，最近通过体内RNAi实验确定了一个对退行性肝病进行治愈性治疗的有前景的靶点。靶向MKK4的小分子领域越来越受到关注。已知几种具有不同骨架的MKK4抑制剂，但很少有具有合理选择性谱和类药性的。为了进一步探索类药MKK4骨架的空间，我们开展了一项广泛的筛选活动，并确定BI-D1870是一个有前景的候选物。二氢蝶啶酮BI-D1870是一种具有广泛脱靶活性的非选择性核糖体S6激酶抑制剂。在本文所述的研究中，我们报告了一种成功的从脱靶到靶向的策略，该策略导致了MKK4的高选择性1,4-二氢吡啶并[3,4-]吡嗪-3(２Ｈ)-酮抑制剂的开发。
