title: Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties.
abstract: Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model.
authors.affiliation: Medicinal Chemistry, Bayer HealthCare AG, Global Drug Discovery, Muellerstraße 178, 13353 Berlin, Germany. Electronic address: ingo.hartung@bayer.com.
authors.forename: Ingo V
authors.initials: IV
authors.lastname: Hartung
authors.affiliation: Therapeutic Research Group Oncology, Bayer HealthCare AG, 13353 Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hammer
authors.affiliation: Medicinal Chemistry, Bayer HealthCare AG, Global Drug Discovery, Muellerstraße 178, 13353 Berlin, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Hitchcock
authors.affiliation: Research Pharmacokinetics, Bayer HealthCare AG, 13353 Berlin, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Neuhaus
authors.affiliation: Therapeutic Research Group Oncology, Bayer HealthCare AG, 13353 Berlin, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Scholz
authors.affiliation: Therapeutic Research Group Oncology, Bayer HealthCare AG, 13353 Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
authors.affiliation: Medicinal Chemistry, Bayer HealthCare AG, Global Drug Discovery, Muellerstraße 178, 13353 Berlin, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bohlmann
authors.affiliation: Structural Biology, Bayer HealthCare AG, 13353 Berlin, Germany.
authors.forename: Roman C
authors.initials: RC
authors.lastname: Hillig
authors.affiliation: Therapeutic Research Group Oncology, Bayer HealthCare AG, 13353 Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Pühler
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D020929:Mitogen-Activated Protein Kinase Kinases; D002256:Carbonic Anhydrases
keywords: Allosteric MEK inhibitor; Blood–plasma ratio; Human carbonic anhydrase; Oncology; Structure-based drug design