4 research outputs found
A highly selective purine-based inhibitor of CSF1R potently inhibits osteoclast differentiation
The colony-stimulating factor 1 receptor (CSF1R) plays an important role in the regulation of many inflammatory
processes, and overexpression of the kinase is implicated in several disease states. Identifying selective, smallmolecule inhibitors of CSF1R may be a crucial step toward treating these disorders. Through modelling, synthesis, and a systematic structure-activity relationship study, we have identified a number of potent and highly
selective purine-based inhibitors of CSF1R. The optimized 6,8-disubstituted antagonist, compound 9, has
enzymatic IC50 of 0.2 nM, and displays a strong affinity toward the autoinhibited form of CSF1R, contrasting that
of other previously reported inhibitors. As a result of its binding mode, the inhibitor shows excellent selectivity
(Selectivity score: 0.06), evidenced by profiling towards a panel of 468 kinases. In cell-based assays, this inhibitor
shows dose-dependent blockade of CSF1-mediated downstream signalling in murine bone marrow-derived
macrophages (IC50 = 106 nM) as well as disruption of osteoclast differentiation at nanomolar levels. In vivo
experiments, however, indicate that improve metabolic stability is needed in order to further progress this
compound class
Synthesis and Development of Highly Selective Pyrrolo[2,3-d]pyrimidine CSF1R Inhibitors Targeting the Autoinhibited Form
Synthetic Routes to Tetrahydrodiazepinopurines - The Heterocyclic Ring System Found in Asmarines
Potent and selective EGFR inhibitors based on 5-aryl-7H-pyrrolopyrimidin-4-amines
The epidermal growth factor receptor represents an important target in cancer therapy, and low molecular weight inhibitors based on quinazolines have reached the marked. Herein we report on a new scaffold, 5-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines, and show that when employing (S)-phenylglycinol as C-4 substituent, potent inhibitors can be made. The two most active inhibitors have suitable druglike properties, were equipotent with Erlotinib in Ba/F3 cell studies, and showed lower cross reactivity than Erlotinib in a panel of 50 kinases