Next Article in Journal
Assessing the Effects of Alloxydim Phototransformation Products by QSAR Models and a Phytotoxicity Study
Next Article in Special Issue
Novel-Substituted Heterocyclic GABA Analogues. Enzymatic Activity against the GABA-AT Enzyme from Pseudomonas fluorescens and In Silico Molecular Modeling
Previous Article in Journal
Isolation of High Purity Anthocyanin Monomers from Red Cabbage with Recycling Preparative Liquid Chromatography and Their Photostability
Previous Article in Special Issue
HIV Resistance Prediction to Reverse Transcriptase Inhibitors: Focus on Open Data
Article Menu
Issue 5 (May) cover image

Export Article

Open AccessArticle
Molecules 2018, 23(5), 992; https://doi.org/10.3390/molecules23050992

Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR/mTOR Kinase Inhibitors

1
Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar-382355, Gujarat, India
2
Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar-382355, Gujarat, India
Dedication: The authors would like to dedicate this paper to Prof. K. S. Viswanathan, IISER Mohali on the occasion of his 65th Birthday.
*
Author to whom correspondence should be addressed.
Received: 20 March 2018 / Revised: 11 April 2018 / Accepted: 13 April 2018 / Published: 24 April 2018
(This article belongs to the Special Issue Recent Trends on Enzymes Inhibitors and Activators in Drug Research)
Full-Text   |   PDF [11391 KB, uploaded 3 May 2018]   |  

Abstract

Targeting DNA damage and response (DDR) pathway has become an attractive approach in cancer therapy. The key mediators involved in this pathway are ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3-related kinase (ATR). These kinases induce cell cycle arrest in response to chemo- and radio-therapy and facilitate DNA repair via their major downstream targets. Targeting ATP-binding site of these kinases is currently under study. Torin2 is a second generation ATP competitive mTOR kinase inhibitor (EC50 = 250 pmol/L) with better pharmacokinetic profile. Torin2 also exhibits potent biochemical and cellular activity against ATM (EC50 = 28 nmol/L) and ATR (EC50 = 35 nmol/L) kinases. In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass analysis. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glo® assay. Additionally, compounds 13 and 14 also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, respectively. Compounds 13 and 14 displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server and validated using PROCHECK, ProSA analysis. Synthesized compounds were docked into the ATP-binding site to understand the binding modes and for the rational design of new inhibitors. View Full-Text
Keywords: DNA damage and repair; ATR; ATM; mTOR; p-Chk1S317 (Ser 317), p70 S6KT389 (Thr 389); homology modeling; docking; molecular dynamic simulation DNA damage and repair; ATR; ATM; mTOR; p-Chk1S317 (Ser 317), p70 S6KT389 (Thr 389); homology modeling; docking; molecular dynamic simulation
Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Shaik, A.; Bhakuni, R.; Kirubakaran, S. Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR/mTOR Kinase Inhibitors. Molecules 2018, 23, 992.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top