IMR Press / FBL / Volume 25 / Issue 8 / DOI: 10.2741/4866

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Article
Evolution of PIKK family kinase inhibitors: A new age cancer therapeutics
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1 Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India, 382355, Indian Institute of Technology Gandhinagar, Gujarat, India 382355
Send correspondence to: Sivapriya Kirubakaran, Discipline of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India, 382355, Tel: 91-9925906242, E-mail: priyak@iitgn.ac.in
Front. Biosci. (Landmark Ed) 2020, 25(8), 1510–1537; https://doi.org/10.2741/4866
Published: 1 March 2020
(This article belongs to the Special Issue Structural genomics of human kinome)
Abstract

Phosphatidylinositol-3 kinase-related kinases (PIKKs) belong to a family of atypical serine/threonine kinases in humans. They actively participate in a diverse set of cellular functions such as meiotic, V(D)J recombination, chromosome maintenance, DNA damage sensing and repair, cell cycle progression and arrest. ATR, ATM, DNA-PKcs, mTOR and hSMG are the members of the PIKK family that play an important role in in cancer cell proliferation, autophagy, and cell survival to radio and chemotherapy. Thereby targeting these PIKK kinases in cancer along with chemo/radiotherapy agents, can help in differential cytotoxicity towards cancer cell over the normal cell. In this review, we compile the various small molecule kinase inhibitors with respect to structural and strategic targeting of PIKK family members. Rapalogs, AZD8055, AZD2014, OSI-027, INK-128, MLN0128, VX970, NVP-BEZ235, Torin2, AZ20, and AZ31 are the diverse scaffolds which have successfully made into the pre-clinical trials either as mono or combinatorial therapy for the treatment of various human cancers. Their synthesis and pre-clinical trial highlight the challenges associated in the development process.

Keywords
Carcinoma
cancer
inhibitors
protein kinases
kinase domain
catalytic activity
Phosphatidylinositol-3 kinase-related kinases
Phosphatidylinositol 3-kinase
Ataxia telangiectasia mutated kinase
ATM- and Rad3-related kinase
DNA dependent protein kinase catalytic subunit
mammalian target of rapamycin (mTOR)
SMG: suppressor with morphological effect on genitalia family member (SMG)
Transformation/transcription-associated protein (TRAAP)
quinolines
clinical trials
pharmacodynamics
pharmacokinetics
IC50
solubility
bioavailability
thiaanthrenpyran-4-one
Rapalogs
pyrazine derivatives
pyrimidine derivatives
schisandrin
caffeine
wortmannin
Auto phosphorylation
DFG motif
Figures
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