Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy

• Published in: European journal of medicinal chemistry 2019-03, Vol.165, p.115-132
• Main Authors: Sonawane, Vinay, Mohd Siddique, Mohd Usman, Jadav, Surender Singh, Sinha, Barij Nayan, Jayaprakash, Venkatesan, Chaudhuri, Bhabatosh
• Format: Article
• Language: English
• Subjects: Cdk4; Dual inhibitor; G0/G1 arrest; G2/M arrest; Quinazolinone; Tubulin polymerization
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.01.011

Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G0/G1 phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells’ ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC50 values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC50 value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC50 of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G0/G1 and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle. [Display omitted] •Dual inhibitors of Cdk4 & tubulin polymerization (TP) identified employing HTVS.•Quinazolinone scaffold selected from the hits of ligand- .→ structure-based HTVS•Four dual inhibitors (29, 34, 40 &50) were identified from enumerated library.•Cink4T (40), inhibited Cdk4 & TP with IC50 of 0.47 and 0.6 μM, respectively.