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Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR/mTOR Kinase Inhibitors
Althaf Shaik1, Rashmi Bhakuni2, Sivapriya Kirubakaran3,4
1Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar-382355, Gujarat, India. althaf.shaik@iitgn.ac.in.
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.
Insights
New Torin2 analogs targeting DNA damage and response (DDR) pathways show promise in cancer therapy. Compounds 13 and 14 exhibit potent anti-cancer activity and inhibit key kinases like ATR and mTOR.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Targeting the DNA damage and response (DDR) pathway is a key strategy in cancer therapy.
- Ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3-related kinase (ATR) are crucial mediators in the DDR pathway.
- Torin2, an mTOR inhibitor, also shows activity against ATM and ATR kinases.
Purpose of the Study:
- To design and synthesize novel Torin2 analogs.
- To evaluate the anti-cancer activity of these analogs.
- To understand the binding modes of synthesized compounds within the ATP-binding site of target kinases.
Main Methods:
- Multistep synthesis of eight Torin2 analogs.
- Characterization using NMR and mass spectrometry.
- In vitro anti-cancer activity evaluation using CellTiter-Glo® assay.
- Inhibition assessment of ATR and mTOR substrates.
- Molecular modeling and docking studies using SWISS-MODEL, PROCHECK, and ProSA.
Main Results:
- Eight new Torin2 analogs were successfully synthesized and characterized.
- Compounds 13 and 14 demonstrated significant inhibition of ATR and mTOR substrates (p-Chk1 Ser 317 and p70 S6K Thr 389).
- Compounds 13 and 14 exhibited promising anti-cancer activity against HCT-116 cell lines.
Conclusions:
- The synthesized Torin2 analogs hold potential as anti-cancer agents.
- Compounds 13 and 14 warrant further investigation for their therapeutic efficacy.
- Molecular docking provided insights for rational design of future DDR pathway inhibitors.
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