2. Academic Validation
  3. Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor

Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor

  • Bioorg Med Chem Lett. 2020 Dec 1;30(23):127517. doi: 10.1016/j.bmcl.2020.127517.
Rashmi Bhakuni 1,  Althaf Shaik 2,  Bhanu Priya 1,  Sivapriya Kirubakaran 3
Affiliations

Affiliations

  • 1 Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gujarat, India.
  • 2 Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India.
  • 3 Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India. Electronic address: priyak@iitgn.ac.in.
PMID: 32911078 DOI: 10.1016/j.bmcl.2020.127517
Abstract

A series of Torin2, a second-generation ATP-competitive inhibitor, analogues were biologically characterized to identify their potential for ATR and mTOR kinase inhibition. Compound SPK 98 was observed to inhibit ATR/mTOR kinase selectively over ATM kinase in HCT 116 cell line. In addition to that, SPK 98 on 30 min incubation with human, mice and rat liver microsomes showed improved properties with an increased half-life (a maximum T ½ of 157 min) and internal clearance in mouse as compared to Torin2. Further, SPK 98 was also noticed to indulge in inducing premature chromatin condensation as a result of ATR/mTOR kinase inhibition at 50 nM. In a nutshell, our work presents the identification and characterization of SPK 98, a small molecule inhibitor, which exhibits improved specific inhibition for ATR at a lower concentration than Torin2.

Keywords

ATM; ATR; Cell cycle arrest; DNA damage response; Premature chromatin condensation.

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