Pan-cancer multi-omics characterization of CDK12 and virtual screening of Vietnamese natural products for novel inhibitors

Abstract

Cyclin-dependent kinase 12 (CDK12), a key regulator of cell-cycle-linked transcriptional programs, has gained increasing attention as a driver of tumorigenesis and a promising therapeutic vulnerability across diverse malignancies. In this study, we combined pan-cancer multi-omics profiling with a computational screen of a Vietnamese medicinal herbs compound library to identify candidate inhibitors targeting both wild-type CDK12 and its drug-resistant C1039F variant. Transcriptomic and proteomic analyses of TCGA and GTEx datasets revealed significant CDK12 overexpression in 14 tumor types compared with matched normal tissues. Overall survival comparisons further indicated that elevated CDK12 expression predicts markedly poorer outcomes in different renal cancer types and glioma, whereas genomic profiling identified ovarian cancer as the malignancy with the highest frequency of CDK12 alterations. Immune deconvolution analyses showed strong associations between CDK12 expression and infiltration by endothelial cells and natural killer T cells, suggesting a link between CDK12 dysregulation and tumor immune evasion. Complementing the multi-omics investigation, molecular docking, molecular dynamics simulations, and MM/PBSA free-energy calculations were conducted to evaluate the binding profiles of natural compounds derived from Vietnamese medicinal plants against both CDK12 variants. Several phytochemicals including 2,3-Diepicastasterone from Phaseolus vulgaris (- 131.038 +/- 23.572 kcal/mol), as well as compounds from Eurycoma longifolia and Oryza sativa-exhibited highly favorable binding affinities and stable interaction dynamics, highlighting them as promising scaffolds for CDK12 inhibitor development. Collectively, our findings establish CDK12 as a robust biomarker for cancer diagnosis, prognosis, and immune modulation, while highlighting natural-product-based scaffolds as promising leads for next-generation CDK12 inhibitors targeting both wild-type and resistant variants, potentially synergizing with emerging immuno-oncology strategies.