Compound 20a(Shanghaitech University)

CDK2 and CDK9 play pivotal roles in cell cycle progression and gene transcription, respectively, making them promising targets for cancer treatment. Herein, we discovered a series of N⁴-(substituted thiazol-2-yl)-N²-(4-substituted phenyl)pyrimidine-2,4-diamines as highly potent CDK2/9 dual inhibitors. Especially, compound 20a significantly inhibited CDK2 (IC₅₀ = 0.004 μM) and CDK9 (IC₅₀ = 0.009 μM), achieving a 1000- and 2800-fold improvement over lead compound 11, and demonstrating broad antitumor efficacy. Mechanistic studies indicated that 20a effectively and simultaneously suppressed CDK2 and CDK9 proteins in the HCT116 cell line, leading to G2/M cell cycle arrest and cell apoptosis by regulating cell cycle- and apoptosis-related protein expression. Most importantly, 20a exhibited 86.7% oral bioavailability in rats and effectively inhibited tumor growth in HCT116 xenograft and C6 glioma rat models without significant toxicity. Overall, these observations clearly confirmed the promising therapeutic strategy of CDK2/9 dual inhibitors and provided a novel potent candidate for cancer therapy.

The GPR139 receptor is an orphan G-protein-coupled receptor (GPCR) mainly found in the central nervous system and is a potential therapeutic target for the treatment of schizophrenia and drug addiction. Guided by the reported structure of GPR139, we conducted medicinal chemistry optimizations of TAK-041, the GPR139 agonist in clinical trials. New compounds with three different core structures were designed and synthesized, and their activity at GPR139 was evaluated. Among them, compounds 15a (EC₅₀ = 31.4 nM) and 20a (EC₅₀ = 24.7 nM) showed potent agonist activity at GPR139 and good pharmacokinetic properties. In murine schizophrenia models, both compounds rescued the social interaction deficits observed in BALB/c mice. Compound 20a also alleviated cognitive deficits in mice with a pharmacologically induced model of schizophrenia. These findings further demonstrated the potential of GPR139 agonists in alleviating the negative symptoms and cognitive deficits of schizophrenia. Compound 20a is worth further evaluation as an antischizophrenia drug candidate.