title: Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories.
abstract: Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901.
authors.affiliation: Medicinal Chemistry, Bayer HealthCare AG, 13353 Berlin, Germany. ingo.hartung@bayer.com
authors.forename: Ingo V
authors.initials: IV
authors.lastname: Hartung
authors.forename: Marion
authors.initials: M
authors.lastname: Hitchcock
authors.forename: Florian
authors.initials: F
authors.lastname: Pühler
authors.forename: Roland
authors.initials: R
authors.lastname: Neuhaus
authors.forename: Arne
authors.initials: A
authors.lastname: Scholz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hammer
authors.forename: Kirstin
authors.initials: K
authors.lastname: Petersen
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
authors.forename: Dominic
authors.initials: D
authors.lastname: Brittain
authors.forename: Roman C
authors.initials: RC
authors.lastname: Hillig
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D047428:Protein Kinase Inhibitors; C506614:mirdametinib; D004159:Diphenylamine; D020930:MAP Kinase Kinase Kinases