Novel hinge binder improves activity and pharmacokinetic properties of BRAF inhibitors.
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.
Zambon
Alfonso
A
The Institute of Cancer Research, Cancer Research UK Centre for Cancer Therapeutics, Sutton, Surrey, UK.
Ménard
Delphine
D
Suijkerbuijk
Bart M J M
BM
Niculescu-Duvaz
Ion
I
Whittaker
Steven
S
Niculescu-Duvaz
Dan
D
Nourry
Arnaud
A
Davies
Lawrence
L
Manne
Helen A
HA
Lopes
Filipa
F
Preece
Natasha
N
Hedley
Douglas
D
Ogilvie
Lesley M
LM
Kirk
Ruth
R
Marais
Richard
R
Springer
Caroline J
CJ
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
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007093:Imidazoles; D010671:Phenylurea Compounds; D011719:Pyrazines; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf