Discovery of N‑Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose

Mutations of the rearranged during
transfection (RET) kinase are
frequently reported in cancer, which make it as an attractive therapeutic
target. Herein, we discovered a series of N-trisubstituted pyrimidine
derivatives as potent inhibitors for both wild-type (wt) RET and RETV804M, which is a resistant mutant for several
FDA-approved inhibitors. The X-ray structure of a representative inhibitor
with RET revealed that the compound binds in a unique pose that bifurcates
beneath the P-loop and confirmed the compound as a type I inhibitor.
Through the structure–activity relationship (SAR) study, compound 20 was identified as a lead compound, showing potent inhibition
of both RET and RETV804M. Additionally, compound 20 displayed potent antiproliferative activity of CCDC6-RET-driven
LC-2/ad cells. Analysis of RET phosphorylation indicated that biological
activity was mediated by RET inhibition. Collectively, N-trisubstituted
pyrimidine derivatives could serve as scaffolds for the discovery
and development of potent inhibitors of type I RET and its gatekeeper
mutant for the treatment of RET-driven cancers.