title: Novel hinge binder improves activity and pharmacokinetic properties of BRAF inhibitors.
abstract: Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A-B-C system featuring an imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A-B-C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations.
authors.affiliation: The Institute of Cancer Research, Cancer Research UK Centre for Cancer Therapeutics, Sutton, Surrey, UK.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Zambon
authors.forename: Delphine
authors.initials: D
authors.lastname: Ménard
authors.forename: Bart M J M
authors.initials: BM
authors.lastname: Suijkerbuijk
authors.forename: Ion
authors.initials: I
authors.lastname: Niculescu-Duvaz
authors.forename: Steven
authors.initials: S
authors.lastname: Whittaker
authors.forename: Dan
authors.initials: D
authors.lastname: Niculescu-Duvaz
authors.forename: Arnaud
authors.initials: A
authors.lastname: Nourry
authors.forename: Lawrence
authors.initials: L
authors.lastname: Davies
authors.forename: Helen A
authors.initials: HA
authors.lastname: Manne
authors.forename: Filipa
authors.initials: F
authors.lastname: Lopes
authors.forename: Natasha
authors.initials: N
authors.lastname: Preece
authors.forename: Douglas
authors.initials: D
authors.lastname: Hedley
authors.forename: Lesley M
authors.initials: LM
authors.lastname: Ogilvie
authors.forename: Ruth
authors.initials: R
authors.lastname: Kirk
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001557:Benzenesulfonates / Q000737:chemistry; D001682:Biological Availability; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011485:Protein Binding; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007093:Imidazoles; D010671:Phenylurea Compounds; D011719:Pyrazines; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf