CDK13 (Cyclin Dependent Kinase 13)

Consequently, elucidating the therapeutic mechanisms of CDK12/13 inhibition has significant translational value for precision oncology. In addition, through bioinformatics techniques, we identified new candidate targets for CDK12/13, contributing to the enrichment of the regulatory network of CDK12/13.

Notably, targeting CDK13 with the small-molecule inhibitor 1NM-PP1 potentiates METTL16 depletion-mediated anticancer effects. Our findings establish a kinase-RNA modifier axis that links CDK13 to epitranscriptomic control of lipid metabolism, positioning the CDK13-METTL16-ACLY pathway as a promising target for precision therapies against ccRCC.

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.

Thus, this study highlights serious challenges posed by GC-rich sequences to site-directed mutagenesis and provides an effective remedy to address such challenges. The findings support that G-quadruplex formation is one mechanism whereby such sequences impede regular PCR-based mutagenesis methods.

Furthermore, we found that p-NUCKS1 was highly expressed in tumor specimens from melanoma patients, and silencing of NUCKS1 inhibited tumor growth in melanoma A375 and A875-bearing mouse models. Therefore, p-NUCKS1 could act as a potential target for melanoma treatment by mediating oxidative stress-induced apoptosis.

In addition, interrogation of the Drug-Gene Interaction Database highlighted putative therapeutic targets such as CDK13, MUC16, and MUC17. While preliminary, these findings establish the first comprehensive mutational blueprint of HNLEC, providing novel insights into its pathogenesis, potential prognostic determinants, and therapeutic vulnerabilities, and laying a foundation for future translational and clinical research.

Notably, the antitumor effects of this combination required STING signaling and functional CD8+ T cells. These findings establish STING activation as the key driver of T cell infiltration and the immune-hot tumor microenvironment in CDK12-mutant cancers, suggesting that dual CDK12/13 inhibitors and degraders activate antitumor immunity and potentiate responses to immunotherapies.

We propose targeted therapies, including GSK3β inhibitors for ALS, antisense oligonucleotides for SCA2, and MTOR modulators for cancer, to restore ATXN2 function. By elucidating phosphocode of ATXN2, this work highlights novel avenues for precision medicine in neurodegenerative and oncogenic diseases.

In silico docking studies revealed a strong and stable interaction with CDK13, with a binding affinity of -8.0 kcal/mol. Compound 4 g demonstrates promising anticancer potential, likely mediated by CDK inhibition with comparatively lower toxicity toward normal cells, however, it requires further toxicological assessment and preclinical studies.

Based on limited single agent activity in preclinical models, trials of new inhibitors should avoid unnecessary exposure of patients to monotherapy and rapidly progress to combination strategies, while retaining designs that allow early evaluation of activity. A framework to support integrated development strategies of new products across sponsors would be very beneficial.

Consistent with in vitro results, 13l significantly repressed tumor growth in an HT-29 xenograft mouse model without causing evident cytotoxicity. Therefore, 13l could be considered as a novel and potentially effective candidate for the future treatment of CRC.