Pyrrolopyrimidines and Purines as CSF1R inhibitors

The colony-stimulating factor 1 receptor (CSF1R) is a tyrosine kinase expressed on the monocyte/macrophage lineages and bone resorbing osteoclasts. Activation of CSF1R and downstream signalling, is necessary for normal function and differentiation of macrophages, microglia and osteoclasts. However, in some diseases, overexpression of CSF-1 and/or elevated activity of CSF1R cause a misbalance of the immune cell phenotypes. Thus, CSF1R inhibitors might be relevant in cancers, CNS and bone diseases. We have investigated pyrrolopyrimidines and purines as CSF1R inhibitors [1-4]. An X-ray co-crystal structure of one of the front runner inhibitors allowed for rational design and identification of a high number of compounds being more active than the reference drug PLX3397 in enzymatic studies. Hurdles for progressing of these inhibitors into lead compounds will be discussed, alongside their kinase activation state preferences.