From off-to on-target: New BRAF-inhibitor-template-derived compounds selectively targeting mitogen activated protein kinase kinase 4 (MKK4)

Eur J Med Chem. 2021 Jan 15;210:112963. doi: 10.1016/j.ejmech.2020.112963. Epub 2020 Oct 24.

Abstract

The mitogen-activated protein kinase (MAP) kinase 4 (MKK4) was found to be a major regulator of liver regeneration and could be a valuable drug target addressing liver related diseases by restoring its intrinsic regenerative capacity. We report on the synthesis and optimization of novel MKK4 inhibitors following a target-hopping strategy from the FDA-approved BRAFV600E inhibitor PLX4032 (8). Applying an iterative multi-parameter optimization process we carved out essential structural features yielding in compounds with a low nanomolar affinity for MKK4 and excellent selectivity profiles against the main off-targets MKK7 and JNK1, which, upon relevant inhibition, would totally abrogate the pro-regenerative effect of MKK4 inhibition, as well as against the off-targets MAP4K5, ZAK and BRAF with selectivity factors ranging from 40 to 430 for our best-balanced compounds 70 and 73.

Keywords: Acute and chronic liver failure; Inhibitors; Liver failure; Liver regeneration; MEK4; MKK4; NAFLD; NASH; Vemurafenib.

MeSH terms

  • Drug Discovery
  • Humans
  • MAP Kinase Kinase 4 / antagonists & inhibitors*
  • MAP Kinase Kinase 4 / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Vemurafenib / analogs & derivatives*
  • Vemurafenib / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Vemurafenib
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase 4