Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, DE, Germany.
Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, DE, Germany; HepaRegenix GmbH, Eisenbahnstraße 63, 72072, Tuebingen, Germany.
Eur J Med Chem. 2022 Oct 5;240:114584. doi: 10.1016/j.ejmech.2022.114584. Epub 2022 Jul 8.
The mitogen-activated protein kinase kinase 4 (MKK4) has recently been identified as druggable target for the treatment of acute liver failure in RNAi experiments. In these experiments MKK4 was identified to be a major regulator in hepatocyte regeneration. Inhibitors thereof may serve as medication to promote liver regeneration or reducing hepatocyte death. Just a small number of potent inhibitors with acceptable selectivity towards relevant off-targets are known up to date. Among the known potent inhibitors, selectivity is highly sensitive towards minor modifications of the molecule, which makes it necessary to carefully balance between potency and selectivity. In the herein presented study, a new class of Vemurafenib-derived inhibitors was investigated with α-carbolines as new scaffold. This new scaffold showed a remarkable intrinsic selectivity towards the chosen off-targets, without affecting potency towards MKK4 on a broad range of structural modifications.
丝裂原活化蛋白激酶激酶 4（MKK4）最近在 RNAi 实验中被确定为治疗急性肝衰竭的可用药靶标。在这些实验中，MKK4 被确定为肝再生的主要调节剂。其抑制剂可能可作为促进肝再生或减少肝细胞死亡的药物。到目前为止，仅已知少数具有可接受的相关脱靶选择性的有效抑制剂。在已知的有效抑制剂中，选择性对分子的微小修饰高度敏感，这使得在效力和选择性之间需要仔细平衡。在本研究中，研究了一类以α-咔啉为新型支架的新型vemurafenib 衍生抑制剂。这种新支架对所选脱靶具有显著的内在选择性，而在广泛的结构修饰中对 MKK4 的效力没有影响。
