Title:Therapeutic Path to Triple Knockout: Investigating the Pan-inhibitory
Mechanisms of AKT, CDK9, and TNKS2 by a Novel 2-phenylquinazolinone
Derivative in Cancer Therapy- An In-silico Investigation Therapy
Volume: 25
Issue: 10
Author(s): Xylia Q. Peters, Ghazi Elamin, Aimen Aljoundi, Mohamed Issa Alahmdi, Nader E. Abo-Dya, Peter A. Sidhom, Ahmed M. Tawfeek, Mahmoud A. A. Ibrahim, Opeyemi Soremekun and Mahmoud E. S. Soliman*
Affiliation:
- Department of Pharmaceutical Science, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
Keywords:
2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one, AKT, CDK9, TNKS2, in silico, inhibitory, flexibility.
Abstract:
Background: Blocking the oncogenic Wnt//β-catenin pathway has of late been investigated
as a viable therapeutic approach in the treatment of cancer. This involves the multi-targeting of certain
members of the tankyrase-kinase family; Tankyrase 2 (TNKS2), Protein Kinase B (AKT), and Cyclin-
Dependent Kinase 9 (CDK9), which propagate the oncogenic Wnt/β-catenin signalling pathway.
Methods: During a recent investigation, the pharmacological activity of 2-(4-aminophenyl)-7-chloro-
3H-quinazolin-4-one was repurposed to serve as a ‘triple-target’ inhibitor of TNKS2, AKT and CDK9.
Yet, the molecular mechanism that surrounds its multi-targeting activity remains unanswered. As such,
this study aims to explore the pan-inhibitory mechanism of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-
4-one towards AKT, CDK9, and TNKS2, using in silico techniques.
Results: Results revealed favourable binding affinities of -34.17 kcal/mol, -28.74 kcal/mol, and -27.30
kcal/mol for 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one towards TNKS2, CDK9, and AKT, respectively.
Pan-inhibitory binding of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one is illustrated by
close interaction with specific residues on tankyrase-kinase. Structurally, 2-(4-aminophenyl)-7-chloro-
3H-quinazolin-4-one had an impact on the flexibility, solvent-accessible surface area, and stability of all
three proteins, which was illustrated by numerous modifications observed in the unbound as well as the
bound states of the structures, which evidenced the disruption of their biological function. Prediction of
the pharmacokinetics and physicochemical properties of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-
one further established its inhibitory potential, evidenced by the favourable absorption, metabolism,
excretion, and minimal toxicity properties.
Conclusion: The following structural insights provide a starting point for understanding the paninhibitory
activity of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one. Determining the criticality of
the interactions that exist between the pyrimidine ring and catalytic residues could offer insight into the
structure-based design of innovative tankyrase-kinase inhibitors with enhanced therapeutic effects.
