CDK2 inhibitors(LifeMine)

Cyclin-dependent kinase 2 (CDK2), a crucial regulator in multiple oncogenic signaling pathways, has emerged as a promising target for the development of innovative anticancer therapies and overcoming resistance to CDK4/6 inhibitors. In this study, three series of compounds were designed and synthesized, using the CDK2 inhibitor fadraciclib (CYC065) as the lead compound, with 9H-purine as the core structure. The design incorporated reported structure-activity relationship data and utilized computer-aided drug design techniques. Compounds in series 1 explored the binding mode between the ATP ribose binding site in CDK2 and C2 substituents, while compounds in series 2 and 3 validated the feasibility of modifying the specific binding region with different substituents and investigated the effects of filling the CDK2 hydrophobic pocket at the N9 position with alkyl substituents. Three compounds, 1f, 2e, and 3a, demonstrated remarkable activity against CDK2-cyclin E2. Notably, 3a exhibited the most potent effect, with a CDK2-cyclin E2 IC₅₀ value of 6.0 ± 0.1 nM, an MV4-11 IC₅₀ value of 489.2 ± 0.2 nM, and excellent selectivity for CDK2. This study evaluated the impact of substitutions at the 2, 6, and 9 positions of the purine ring on the activity of CDK2 small molecule inhibitors. The findings offer a theoretical foundation for future research, broadening the structural diversity and scope of CDK2 inhibitor studies.

In the current medical era, CDK2 kinase has emerged as a promising target in the global fight against cancer. Recent research reported the overexpression of CDK2 in prostate cancer cells, which highlighted the potential of CDK2 inhibition as a practical therapeutic approach for this disease that stands out as a challenging global health issue. On account of their interesting biological activities, especially anti-cancer properties, the two privileged scaffolds benzothiazole and pyrazolo[1,5-a]pyrimidine were utilized in this study to develop three series of 16 novel small molecules (8a-k, 12a-c, and 14a-b) as potential anti-prostate cancer agents targeting CDK2. The synthesized derivatives were assessed for cytotoxic effects against two prostate cancer cell lines, DU-145 and PC-3. Compounds 8f, 12c, and 14b exhibited the highest anti-cancer activity. Further investigation showed that these molecules inhibit critical cell cycle regulators by arresting DU-145 cells at the G0/G1 phase. Apoptosis induction was verified using Annexin V-FITC/Propidium iodide (PI) assays, which indicated a noteworthy apoptosis level in DU-145 cells. The compounds were validated as CDK2 inhibitors via in-vitro assays, with 8f demonstrating the highest potency, exceeding that of the reference drug Roscovitine. Molecular docking studies revealed substantial binding affinities of compounds 8f, 12c, and 14b to the ATP-binding site of CDK2, supported by essential hydrogen bonding and hydrophobic interactions. Overall, these study's findings indicate the potential of these benzothiazole-grafted pyrazolo[1,5-a]pyrimidines as effective therapeutic agents for prostate cancer.