TY - JOUR
T1 - Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose
AU - Zhang, Lingtian
AU - Moccia, Marialuisa
AU - Briggs, David C.
AU - Bharate, Jaideep B.
AU - Lakkaniga, Naga Rajiv
AU - Knowles, Phillip
AU - Yan, Wei
AU - Tran, Phuc
AU - Kharbanda, Anupreet
AU - Wang, Xiuqi
AU - Leung, Yuet Kin
AU - Frett, Brendan
AU - Santoro, Massimo
AU - McDonald, Neil Q.
AU - Carlomagno, Francesca
AU - Li, Hong Yu
N1 - Funding Information:
This work was supported by the Grant NCI 1R01CA197178. N.Q.M. was also supported by the Francis Crick Institute, which receives its core funding (FC001115) from the Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. Finally, we would like to thank Dr. Zhiqiang Qin at UAMS for the permission to use their flow cytometry instrument.
Publisher Copyright:
© 2022 American Chemical Society
PY - 2022/1/27
Y1 - 2022/1/27
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.1c01280
DO - 10.1021/acs.jmedchem.1c01280
M3 - Article
C2 - 35081714
AN - SCOPUS:85123904871
VL - 65
SP - 1536
EP - 1551
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 2
ER -