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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 20was identified as a lead compound, showing potent inhibition of both RET and RETV804M. Additionally, compound 20displayed 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.

The ability of wild-type and not mutant p53 to exert antiproliferative effects on normal cells may be related to a difference in the conformational state of the protein. We have used pure, human wild-type p53 and a panel of monoclonal antibodies whose epitopes map throughout the protein to assess whether divalent metal ions affect the conformation of p53. Our results show that the presence of Zn2+ions at physiological concentrations, directly reduced or blocked accessibility of epitopes on pure wild-type p53, an effect which was reversed by chelating agents. Loss of epitope reactivity was maximal between the protein mid-region and C-terminus. Analytical sucrose density gradient ultracentrifugation studies also confirmed that Zn2+-induced conformational changes partially affected the pattern of p53 oligomerisation. The observed binding of pure p53 to a sequence-specific DNA motif was unaffected by the presence of added Zn2+ions or metal chelating agents.

An examination of the activity profiles of RET inhibitors suggests potential treatment for RET-rearranged cancers.

A cancer-associated mutation in protein kinase Cι selectively disrupts epithelial polarity by inhibiting the binding of specific substrates.