Evolution of PIKK family kinase inhibitors: A new age cancer therapeutics

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