seliciclib (CYC202)

Leads 12c, 12i, and 22 demonstrated potent kinase inhibition, with 22 yielding a CDK-2 IC₅₀ of 0.03 µM (seliciclib: 0.02 µM), and 12c delivering an EGFR IC₅₀ of 0.12 µM (erlotinib: 0.01 µM). Promising ADMET profiles and good drug likeness are evident in these leads. These data underscore the great potential of this scaffold for developing dual EGF/CDK-2 inhibitors aimed at resistance mechanisms in more aggressive cancers and can thus be pursued further in preclinical optimization.

Among the tested analogs, 6e, 6f, and 6 g exerted promising cytotoxicity toward HS 578 T cells where compound 6f exhibited significant antiproliferative activity with an IC50 of 3.06 µM, exceeding that of Lapatinib by 7.6 fold...The findings illustrated that analog 6f exerted the most potent CDK-2 inhibition with an IC50 equal to 0.277 µM, which is approximately threefold the activity of Roscovitine (0.833 µM). As well, compound 6f arrested HS 578 T cell cycle at both S and G2/M phases and stimulated apoptosis by increasing Bax and Caspase-3 expression with a concurrent decline in the expression of Bcl-2. Additionally, ADMET prediction and the binding interaction of the most active derivatives with CDK-2 have been studied in silico to evaluate their potential as important antitumor agents.

Exploratory drug-response modeling with pRRophetic suggested lower estimated half-maximal inhibitory concentration (IC50) values for agents including MS-275 (entinostat), PF-4708671, and roscovitine in the high-risk group. The TIDE algorithm carries prognostic information in NSCLC beyond immunotherapy settings. The proposed TIDE-informed gene signature reproduced prognostic stratification across cohorts, suggesting potential applicability to a broader NSCLC population and supporting future personalized risk stratification.

The CDK2 inhibitory evaluation of pyrazolo[3,4-b]pyridines 6a-g and 7a-f revealed that compounds 6e, 7b, and 7c exhibited potent inhibition (IC₅₀ = 0.88, 1.89, and 1.23 μM, respectively), compared to roscovitine (IC₅₀ = 0.84 μM). Among the spiro-oxindole derivatives 8a-d, compounds 8b and 8c demonstrated remarkable EGFR inhibition (IC₅₀ = 0.13 and 0.09 μM, respectively) and significant activity against mutant EGFRT790M (IC₅₀ = 0.32 and 0.14 μM) relative to gefitinib (IC₅₀ = 0.03 and 0.18 μM, respectively)...Molecular docking studies combined with molecular dynamics simulations further supported stable ligand-protein interactions within CDK2, EGFR, and mutant EGFRT790M active sites, with favorable binding energies and conformational stability throughout 100 ns trajectories. Collectively, these findings identify compounds 6e and 8c as promising lead scaffolds for further development of CDK2 or EGFR inhibitors with potent and selective anticancer properties.

The potency of compound 4p (IC50 = 148 nM) against CDK2 was much higher than that of roscovitine (IC50 = 700 nM)...ADMET projections further highlighted positive drug-like qualities. Taking together, compound 4p is a promising anticancer candidate that targets CDK2 and exhibits strong in vivo efficacy, with supporting molecular evidence.

These findings demonstrate that Roscovitine potentiates anti-PD-1 therapy by simultaneously suppressing immunosuppressive cell populations and amplifying effector immune responses. The dual modulation of PD-L1 expression and immune cell dynamics provides a strong rationale for the clinical evaluation of Roscovitine in combination with immune checkpoint blockade in NSCLC and potentially other solid tumors.

Sorafenib, Salubrinal, and Roscovitine were positively correlated with the risk score, whereas WO2009093972 was negatively correlated. Additionally, this study identified several target genes such as FBXO25 with TINAG, CCDC28A with EPHB2, and SH2D6 with FCN3, with subsequent validation achieved through qPCR and western blotting. In conclusion, this study identifies three prognostic genes, providing new insights into CRC pathogenesis and potential therapeutic strategies.

Among the tested compounds, 7-(4-bromophenyl)-2-(methylthio)pyrazolo[1,5-a]pyrimidine-3‑carbonitrile (13 g), 7-(2,4-dichlorophenyl)-2-(methylthio)pyrazolo[1,5-a]pyrimidine-3‑carbonitrile (13j), 7-[1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-2-(methylthio)pyrazolo[1,5-a] pyrimidine-3‑carbonitrile (21c), and 7-(6-bromo-2-oxo-2H-chromen-3-yl)-2-(methylthio)pyrazolo[1,5-a] pyrimidine-3‑carbonitrile (26b) exhibited strong growth inhibition in HCT-116 cells, comparable to the reference drug roscovitine...Molecular docking studies supported these results, showing favorable interactions of compound 21c within the CDK2 active site. Overall, compound 21c emerges as a promising lead candidate for the development of selective CDK2 inhibitors exhibiting potent anti-cancer activity and low toxicity toward normal cells.

AS601245, AP.24534 and roscovitine were the top three chemotherapeutic agents showing the highest sensitivity differences between the risk groups. The RT-qPCR results indicated that the expression of electron transfer flavoprotein subunit α, rap guanine nucleotide exchange factor-like 1, keratin 7, cluster of differentiation 24, proline rich 15-like, arachidonate 15-lipoxygenase type B, ELOVL fatty acid elongase 2 and C-X-C motif chemokine ligand 9 was consistent with the results of bioinformatic analysis. In conclusion, the HER2-related risk model and nomogram developed in the present study demonstrated high accuracy in predicting patient survival.

However, they displayed a dose-dependent inhibition of CDK2 kinase activity in in-vitro ADP-Glo™ assay with IC50 values of 23.47 and 82.04 nM, respectively, compared to 0.51 and 700 nM for Dinaciclib and Roscovitine, respectively. Compound 6 downregulated CDK2 protein targets involved in DNA replication process; Polα, MCM7, ORC2, and ORC4 in CRC cell lines. Subjected to cell cycle analysis, HCT-116 and HT-29 treated with compound 6 demonstrated pre-G1 phase arrest with no similar observation in S phase.

A key finding from drug sensitivity analysis was that the high-risk group exhibited significantly increased sensitivity to several drugs, including CCT018159, rapamycin, vinblastine, metformin, and roscovitine. Moreover, the expression levels of SESN3, CRIP1, DPP4 and PIK3CA were significantly upregulated in breast cancer samples compared to control samples. This study constructed a risk model based on seven prognostic genes, offering new potential strategies for breast cancer therapy.

Compounds 4, 7, and 10 revealed significant CDK2 inhibitory activities with comparable potencies (IC50 = 0.75, 0.77 and 0.85 µM, respectively) to that of roscovitine (IC50 = 0.99 µM)...Further investigation on the mechanism demonstrated that 5 induced apoptosis, increased the proapoptotic protein Bax level, and reduced the antiapoptotic Bcl-2 level in the cells of MCF-7. Finally, the molecular docking study showed bioactive analogues that fit well in the CDK2 active site via various interactions.