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Updated: Dec 27, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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Evolution of PIKK family kinase inhibitors: A new age cancer therapeutics

Althaf Shaik1, Sivapriya Kirubakaran2

  • 1Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India, 382355, Indian Institute of Technology Gandhinagar, Gujarat, India 382355.

Frontiers in Bioscience (Landmark Edition)
|March 2, 2020
PubMed

Insights

Targeting Phosphatidylinositol-3 kinase-related kinases (PIKKs) with small molecule inhibitors shows promise for cancer therapy. These inhibitors, including various scaffolds, are being explored in preclinical trials for enhanced cancer cell cytotoxicity.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Phosphatidylinositol-3 kinase-related kinases (PIKKs) are crucial atypical serine/threonine kinases involved in vital cellular processes.
  • Key PIKK family members (ATR, ATM, DNA-PKcs, mTOR, hSMG) are implicated in cancer proliferation, survival, and resistance to therapy.

Purpose of the Study:

  • To review small molecule kinase inhibitors targeting PIKK family members for cancer treatment.
  • To explore structural and strategic approaches for PIKK inhibition in oncology.

Main Methods:

  • Compilation of diverse small molecule kinase inhibitors.
  • Analysis of inhibitors' structural and strategic targeting of PIKKs.
  • Review of preclinical trial data for PIKK-targeted agents.

Main Results:

  • Identified various scaffolds like Rapalogs, AZD8055, and Torin2 that have entered preclinical trials.
  • Demonstrated the potential of PIKK inhibitors as monotherapy or in combination with chemo/radiotherapy.
  • Highlighted the role of PIKK targeting in achieving differential cytotoxicity against cancer cells.

Conclusions:

  • Small molecule inhibitors targeting PIKKs represent a promising strategy for cancer therapy.
  • Further development and clinical trials are necessary to overcome challenges in PIKK inhibitor development.

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