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

[Image: see text] 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 IC(50) values of 0.93 and 0.83 μM, respectively, and >20-fold selectivity over CDK2/E1 (IC(50) > 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.