title: 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.
authors.affiliation: Medicinal Chemistry Berlin, Bayer HealthCare AG, 13353, Berlin, Germany. ingo.hartung@bayer.com.
authors.forename: Ingo V
authors.initials: IV
authors.lastname: Hartung
authors.affiliation: Global Therapeutic Research Group Oncology, Bayer HealthCare AG, 13353, Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Pühler
authors.affiliation: Research Pharmacokinetics, Bayer HealthCare AG, 13353, Berlin, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Neuhaus
authors.affiliation: Global Therapeutic Research Group Oncology, Bayer HealthCare AG, 13353, Berlin, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Scholz
authors.affiliation: Global Therapeutic Research Group Oncology, Bayer HealthCare AG, 13353, Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
authors.affiliation: Medicinal Chemistry Berlin, Bayer HealthCare AG, 13353, Berlin, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Geisler
authors.affiliation: Structural Biology, Bayer HealthCare AG, 13353, Berlin, Germany.
authors.forename: Roman C
authors.initials: RC
authors.lastname: Hillig
authors.affiliation: Global Biomarker Research, Bayer HealthCare AG, 13353, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: von Ahsen
authors.affiliation: Medicinal Chemistry Berlin, Bayer HealthCare AG, 13353, Berlin, Germany. marion.hitchcock@bayer.com.
authors.forename: Marion
authors.initials: M
authors.lastname: Hitchcock
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous
chemical_list: D001549:Benzamides; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C506614:mirdametinib; D004159:Diphenylamine; D048369:MAP Kinase Kinase 1
keywords: MEK; feedback activation; inhibitors; kinases; oncology; structure-based drug design