- SAR study on: N 2, N 4-disubstituted pyrimidine-2,4-diamines as effective CDK2/CDK9 inhibitors and antiproliferative agents
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Cyclin-dependent kinases (CDKs) are pivotal kinases in cell cycle transition and gene transcription. A series of N2,N4-diphenylpyrimidine-2,4-diamines were previously identified as potent CDK2/CDK9 inhibitors. To explore the SAR of this structural prototype, twenty-four novel N2,N4-disubstituted pyrimidine-2,4-diamines were designed and synthesized. Among them, twenty-one compounds exhibited potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems, and the most potent CDK2 and CDK9 inhibitors, 3g and 3c, showed IC50 values of 83 nM and 65 nM respectively. Most of these compounds displayed significant inhibition against the tested tumor cell lines in the SRB assay, and in particular, remained active against the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometer analysis of compounds 2a, 2d and 3b in MDA-MB-231 cells indicated that these compounds induced cell cycle arrest in G2/M phase. Docking studies on compound 3g were performed, which provided conducive clues for further molecular optimization.
- Jing, Liandong,Tang, Yanbo,Goto, Masuo,Lee, Kuo-Hsiung,Xiao, Zhiyan
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p. 11871 - 11885
(2018/04/12)
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- COMPOUNDS
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A compound of formula (I): compositions and medicaments containing the same as well as processes for the preparation and use of such compounds, compositions and medicaments, particularly in diseases associated with inappropriate Aurora activity.
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Page/Page column 71-72
(2010/11/26)
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- HETEROCYCLIC MODULATORS OF NUCLEAR RECEPTORS
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Compounds, compositions and methods for modulating the activity of nuclear receptors are provided. In particular, heterocyclic compounds are provided for modulating the activity of farnesoid X receptor (FXR), liver X receptor (LXR) and/or orphan nuclear receptors. In certain embodiments, the compounds are thiazolidinone derivatives.
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