SAR study on N²,N⁴-disubstituted pyrimidine-2,4-diamines as effective CDK2/CDK9 inhibitors and antiproliferative agents

Abstract

Novel pyrimidine-2,4-diamine derivatives were identified as potent CDK9 and CDK2 inhibitors, and were active against tumor cells including MDA-MB-231.

Discovery of Orally Bioavailable and Potent CDK9 Inhibitors for Targeting Transcription Regulation in Triple-Negative Breast Cancer

“…Despite several significant advancements in targeting CDKs as novel approaches and promising treatment options against TNBC (Figure B,C; compound 1 – 6 − ), there remains a shortage of CDK9 modulators specifically designed for TNBC treatment, and most of these inhibitors either exhibit only moderate potency or target other subtypes of CDKs (especially CDK2, a cell cycle-related CDK with 40% sequence identity to CDK9). − For example, dinaciclib (also named SCH727965 or MK-7965), which progressed into three TNBC-related clinical trials (phase 1 or phase 2; ClinicalTrials.gov ID: NCT00732810, NCT01624441, NCT01676753), have similar inhibitory activity against CDK2 and CDK9 (IC 50 = 1 and 4 nM, respectively); fadraciclib (CYC065), being tested in an ongoing clinical trial on advanced solid tumors, including TNBC (phase 1/2; ClinicalTrials.gov ID: NCT04983810), also targets both CDK2 and CDK9 (IC 50 = 5 and 26 nM, respectively) . Indeed, off-target inhibition might result in side effects and unexpected toxicity, thereby narrowing the therapeutic window and compromising the potential for developing targeted therapeutics; principally, the development of selective inhibitors offers various benefits, including providing specific insight into the mechanism of action, refining patient selection criteria, and facilitating the establishment of a specific therapeutic window .…”

Physicochemical properties of some pyrimidine derivatives in some organic solvents

“…These compounds are known to possess wide spectrum of biological activities such as anti-tubercular, anti-HIV, anti-microbial, anti-analgesic, anti-inflammatory and antimalarial, antidepressant, anticonvulsant, antioxidant, anticancer, antifungal, etc. [4][5][6][7][8][9][10][11][12][13][14][15][16] .…”