Discovery of Pongol, the Furanoflavonoid, as an Inhibitor of CDK7/Cyclin H/MAT1 and Its Preliminary Structure-Activity Relationship.

ABSTRACT: Natural products have been a great source of leads for cancer drug discovery. The cyclin-dependent kinases (CDKs) play a vital role in the initiation and progression of cancer. The CDK-activating kinase, CDK7/cyclin H/MAT1, has recently gained tremendous attention in targeted cancer drug discovery. Herein, we screened a small library of pure natural products in an ADP-Glo CDK7/H kinase assay that yielded a series of furano- and naphthoflavonoids among actives. Pongol (SBN-88), the hydroxy-substituted furanoflavonoid, inhibits CDK7/H as well as CDK9/T1 with IC₅₀ values of 0.93 and 0.83 μM, respectively, and >20-fold selectivity over CDK2/E1 (IC₅₀ > 20 μM). The molecular docking and molecular dynamics simulation revealed that the presence of phenolic -OH in pongol is vital for kinase inhibition, as its absence resulted in a significant loss in activity (e.g., lanceolatin B). The prime MM-GBSA calculations revealed the presence of strong lipophilic and H-bonding interactions of pongol with CDKs.

SUBMITTER: Bhurta D 

PROVIDER: S-EPMC9835647 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature