Modular Assembly of Allosteric MEK Inhibitor Structural Elements Unravels Potency and Feedback‐Modulation Handles

Abstract

Having recently identified a so-far unexplored area adjacent to the known binding site of allosteric mitogen-activated protein kinase kinase (MEK) inhibitors, we now report an extension of these studies by combining our new side chains with different MEK inhibitor cores in a modular manner. Replacement of the amide headgroup with inverse sulfonamides resulted in the identification of new MEK inhibitors with at least 10-fold higher cellular potency against K-Ras-mutated tumor cells. A selected inhibitor from this new series retained the favorable pharmacokinetic profile of its predecessor in rodent and non-rodent species and displayed significant in vivo efficacy at once-daily oral doses of 0.25-1 mg kg(-1) in a K-Ras-mutated xenograft model. The brain penetration potential of this analogue was significantly attenuated relative to PD325901. In a second series, the central fluorophenyl core was replaced by a pyridine moiety which gave rise to a similar boost in cellular potency. Most notably, analogues from this second series do not show MEK feedback phosphorylation in K-Ras-mutated A549 cells. Our results complement recent reports on the structural intricacies of MEK-Raf feedback interactions.

A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding

“…22) allowing unambiguous determination of transcript isoforms. A MAPK/ERK kinase (MAP2K, MEK) inhibitor (MEKI) 58 was applied to probe the effect of TGF-β by blocking the downstream signalling cascade. Consistent with our short-read (Illumina sequencing) dataset of THESC decidualization, the enriched pathways of differentially expressed genes (padj < 0.05, abs(log2FC) ≥ 1.5) include cell cycle and chromosome segregation (Supplementary Fig.…”

“…Inhibition of uterine bleeding in vivo was performed by p.o. application of MEK inhibitor (BAY MEKi, cpd 26 58 , Bayer AG, Germany) at doses of 0.5 mg/kg daily or ACVR1 inhibitor (TP-0184, Toledo Pharmaceuticals, USA) at doses of 15 mg/kg daily dissolved in N-methyl-2-pyrrolidone (NMP)/ polyethylene glycol 400 (PEG400) (1/9) (d0-d15). Controls were treated with vehicle alone.…”