Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

Mohd Yousuf; Parvez Khan; Anas Shamsi; Mohd Shahbaaz; Gulam Mustafa Hasan; Qazi Mohd Rizwanul Haque; Alan Christoffels; Asimul Islam; Md Imtaiyaz Hassan

doi:10.1021/acsomega.0c03975

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

ACS Omega. 2020 Oct 14;5(42):27480-27491. doi: 10.1021/acsomega.0c03975. eCollection 2020 Oct 27.

Authors

Mohd Yousuf¹, Parvez Khan², Anas Shamsi², Mohd Shahbaaz^{3

4}, Gulam Mustafa Hasan⁵, Qazi Mohd Rizwanul Haque¹, Alan Christoffels³, Asimul Islam², Md Imtaiyaz Hassan²

Affiliations

¹ Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
² Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
³ South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa.
⁴ Laboratory of Computational Modeling of Drugs, South Ural State University, 76 Lenin Prospekt, Chelyabinsk 454080, Russia.
⁵ Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.

Abstract

Cyclin-dependent kinase 6 (CDK6) is a potential drug target that plays an important role in the progression of different types of cancers. We performed in silico and in vitro screening of different natural compounds and found that quercetin has a high binding affinity for the CDK6 and inhibits its activity with an IC₅₀ = 5.89 μM. Molecular docking and a 200 ns whole atom simulation of the CDK6-quercetin complex provide insights into the binding mechanism and stability of the complex. Binding parameters ascertained by fluorescence and isothermal titration calorimetry studies revealed a binding constant in the range of 10⁷ M^-1 of quercetin to the CDK6. Thermodynamic parameters associated with the formation of the CDK6-quercetin complex suggested an electrostatic interaction-driven process. The cell-based protein expression studies in the breast (MCF-7) and lung (A549) cancer cells revealed that the treatment of quercetin decreases the expression of CDK6. Quercetin also decreases the viability and colony formation potential of selected cancer cells. Moreover, quercetin induces apoptosis, by decreasing the production of reactive oxygen species and CDK6 expression. Both in silico and in vitro studies highlight the significance of quercetin for the development of anticancer leads in terms of CDK6 inhibitors.