Discovery of a Dual-Target Inhibitor of CDK7 and HDAC1 That Induces Apoptosis and Inhibits Migration in Colorectal Cancer

ChemMedChem. 2023 Dec 1;18(23):e202300281. doi: 10.1002/cmdc.202300281. Epub 2023 Oct 25.

Abstract

Aberrant expression or dysfunction of cyclin-dependent kinase 7(CDK7) and histone deacetylase 1 (HDAC1) are associated with the occurrence and progression of various cancers. In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer strong support for the development of dual-target inhibitors of CDK7 and HDAC1 and provide a promising avenue for future cancer therapy.

Keywords: CDK7; HDAC1; apoptosis; colorectal cancer; dual-target inhibitors; migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms* / drug therapy
  • Cyclin-Dependent Kinases
  • Histone Deacetylase 1
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans

Substances

  • Cyclin-Dependent Kinases
  • Antineoplastic Agents
  • Histone Deacetylase 1
  • Histone Deacetylase Inhibitors
  • HDAC1 protein, human