Four protein kinase inhibitors, R547, GDC-0879, JNJ-7706621 and ABT-869 were found to bind hPIP5K1α via a stable complex formation. The hit molecules display favorable ADME properties and are predicted to be non-carcinogenic. The hit molecules in particular R547, have better binding free energies compared to reference molecule, ISA-2011B.

We tested these bifunctionals in a FKBP(F36V)-tagged transcription factor reporter system and found bifunctional induced transactivation is relatively common, being observed for bifunctionals with BET ligand JQ1, p300/CBP ligand GNE-781, CDK9 ligand SNS-032, and BRD9 ligand iBRD9. Together, these data establish bifunctionals targeting p300/CBP that toggle between a program of ultra-potent transactivation and repression depending on cellular context. Overall demonstrating that induced proximity with a given ligand does not encode a fixed functional outcome.

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 anti-tumor effects of dinaciclib were confirmed in an in vivo xenograft model. Overall, this study demonstrates that dinaciclib effectively targets ATL cells by inducing MCL-1 deregulation and promoting apoptotic cell death.

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.

P2, N=124, Recruiting, Alliance for Clinical Trials in Oncology | Trial primary completion date: Jan 2026 --> Jan 2027

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.

THBS3-high breast cancer patients exhibited resistance to Dinaciclib, Daporinad, and Rapamycin. THBS3 may promote breast cancer progression through immune regulation, ECM remodeling, and drug resistance mechanisms, suggesting its potential as a therapeutic target. These findings support enhanced breast cancer screening in IBD patients.

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.