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.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Hartung IV,Pühler F,Neuhaus R,Scholz A,Siemeister G,Geisler J,Hillig RC,von Ahsen O,Hitchcock Mdoi
10.1002/cmdc.201500442subject
Has Abstractpub_date
2015-12-01 00:00:00pages
2004-13issue
12eissn
1860-7179issn
1860-7187journal_volume
10pub_type
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