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

被引:4
|
作者
Bhurta, Deendyal [1 ,2 ]
Bharate, Sandip B. [1 ,2 ]
机构
[1] CSIR Indian Inst Integrat Med, Nat Prod & Med Chem Div, Jammu 180001, India
[2] Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India
来源
ACS OMEGA | 2023年 / 8卷 / 01期
关键词
BREAST-CANCER; IDENTIFICATION; FLAVOPIRIDOL; RECEPTOR; PROTEIN; LIGAND;
D O I
10.1021/acsomega.2c06733
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 mu M, respectively, and >20-fold selectivity over CDK2/E1 (IC50 > 20 mu M). 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.
引用
收藏
页码:1291 / 1300
页数:10
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