RTI uses cookies to offer you the best experience online. By clicking “accept” on this website, you opt in and you agree to the use of cookies. If you would like to know more about how RTI uses cookies and how to manage them please view our Privacy Policy here. You can “opt out” or change your mind by visiting: http://optout.aboutads.info/. Click “accept” to agree.
Highly selective MERTK inhibitors achieved by a single methyl group
Zhao, J., Zhang, D., Zhang, W., Stashko, M. A., DeRyckere, D., Vasileiadi, E., Parker, R. E., Hunter, D., Liu, Q., Zhang, Y., Norris-Drouin, J., Li, B., Drewry, D. H., Kireev, D., Graham, D. K., Earp, H. S., Frye, S. V., & Wang, X. (2018). Highly selective MERTK inhibitors achieved by a single methyl group. Journal of Medicinal Chemistry, 61(22), 10242-10254. https://doi.org/10.1021/acs.jmedchem.8b01229
Although all kinases share the same ATP binding pocket, subtle differences in the residues that form the pocket differentiate individual kinases' affinity for ATP competitive inhibitors. We have found that by introducing a single methyl group, the selectivity of our MERTK inhibitors over another target, FLT3, was increased up to 1000-fold (compound 31). Compound 19 was identified as an in vivo tool compound with subnanomolar activity against MERTK and 38-fold selectivity over FLT3 in vitro. The potency and selectivity of 19 for MERTK over FLT3 were confirmed in cell-based assays using human cancer cell lines. Compound 19 had favorable pharmacokinetic properties in mice. Phosphorylation of MERTK was decreased by 75% in bone marrow leukemia cells from mice treated with 19 compared to vehicle-treated mice.