CDK9 (Cyclin Dependent Kinase 9)

Oroxylin A and donafenib exert a synergistic anti-tumor effect in HCC by co-activating the TP53 signaling pathway through distinct but complementary molecular axes. This combination strategy presents a promising and viable therapeutic approach to overcome the limitations of donafenib monotherapy in the treatment of HCC.

Strategic structural modifications significantly enhance the potency, selectivity, and pharmacokinetics of anti-TNBC agents. Future research should emphasize polypharmacology, advanced delivery strategies, and translational validation to address TNBC heterogeneity.

A few were predicted to be carcinogenic, immunotoxic, and/or cytotoxic. Overall, the clerodane-type furano-diterpenoids from T. crispa show encouraging results in in-silico studies and may be considered for further modification and lead development.

These experiments led to the identification of a novel compound exhibiting interesting therapeutic potential, both as a single agent and in combination with Camptothecin (CPT), revealing varying response profiles across the tested cell lines. These results illustrate the power of integrating ML within anticancer drug discovery pipelines and represent a valuable starting point for the development of novel CDK9 inhibitors.

In addition, WWZ-11-098 displayed favorable pharmacokinetic properties (Cmax = 11833 ng/mL, T1/2 = 2.64 h after a 5 mpk IV dose) and exhibited robust antitumor efficacy (TGI: 77.1 % @10 mpk) in a MOLT-4 xenograft model without signs of toxicity. The compound provides not only a valuable chemical probe but also a lead structure for further development of CDK6 degraders.

Molecular docking analyses further supported these findings by demonstrating strong binding affinities of phytochemicals to key cell cycle regulatory proteins, suggesting a direct molecular basis for their antiproliferative effects. In conclusion, the n-butanol fraction of Ardisia villosa displays potent anticancer activity, particularly in gastric cancer cells, through multi-targeted mechanisms involving cell cycle inhibition and senescence induction, and holds promise as a natural source for future anticancer therapeutics.

Our results position CDK9 as a promising therapeutic target in TNBC, either alone or in combination with EGFR inhibition, provided that side effects associated with this combination treatment can be controlled.

ZMYM3 S464 emerges as a phospho-regulatory hub that coordinates epigenetic silencing, HR repair, and mitotic fidelity. Its cancer-type-specific upregulation offers a novel biomarker for HR-deficiency stratification and a therapeutic entry point for modulating BRCA1 function or epigenetic drug sensitivity; functional validation in HR-deficient models is now warranted.

These findings prove the highly synergistic mechanism of action of RVU120+VEN combination and the potential to overcome primary/acquired VEN resistance in relapse/refractory AML disease. Altogether, the presented results support ongoing clinical studies evaluating romaciclib and VEN in VEN/HMA-refractory patients ( NCT06191263 ) and provide a basis for future exploration as a frontline therapy in VEN-naïve patients.

Furthermore, HS-36 possessed an excellent pharmacokinetic profile, including good oral bioavailability (F = 41.8%), which enabled solid and well-tolerated in vivo antitumor efficacy (TGI = 68.8%) in a MV-4-11 xenograft model. This work not only presents HS-36 as a promising lead compound but also validates our rational approach to optimizing natural product scaffolds.

Transcriptional addiction is an important feature in the process of oral mucosal carcinogenesis. Targeting this CDK9-dependent transcriptional addiction induces cell apoptosis by downregulating ADA, and thereby interfering the enzymatic conversion of adenosine to inosine to hamper oral mucosal carcinogenesis.

A HB patient-derived xenograft (PDX) model was treated with placebo, vincristine + irinotecan (VI), dinaciclib, or VI + dinaciclib to evaluate tumor growth and response to therapy. In our PDX model, treatment with VI + dinaciclib resulted in decreased tumor volume, viability and HB cell proliferation. Given these findings, combination treatment with VI and dinaciclib should be investigated further as a treatment for chemoresistant HB.