Potency and pharmacokinetics of broad spectrum and isoform-specific p110γ and δ inhibitors in cancers

Journal of Receptor and Signal Transduction Research
Aravind SettiSmita C Pawar

Abstract

Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110γ and p110δ catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110δ structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2 ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110γ and p110δ, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, m...Continue Reading

References

Jan 30, 1978·Archives of Biochemistry and Biophysics·F C BernsteinM Tasumi
Sep 1, 1997·Nucleic Acids Research·S F AltschulD J Lipman
Dec 5, 1998·Biochimica Et Biophysica Acta·M P Wymann, L Pirola
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Mar 15, 2002·Trends in Biochemical Sciences·David T Jones, Mark B Swindells
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 20, 2004·Quarterly Reviews of Biophysics·James C Whisstock, Arthur M Lesk
Feb 11, 2005·Bioinformatics·Alasdair T R Laurie, Richard M Jackson
May 26, 2006·Journal of Medicinal Chemistry·René Thomsen, Mikael H Christensen
Oct 21, 2006·Biochemical Society Transactions·P T HawkinsL R Stephens
Nov 3, 2006·Nature Reviews. Drug Discovery·Thomas RückleChristian Rommel
Sep 12, 2007·Bioinformatics·M A LarkinD G Higgins
Nov 13, 2007·Biochimica Et Biophysica Acta·Romina MaroneMatthias P Wymann
Aug 30, 2008·Current Opinion in Pharmacology·Timothy A YapPaul Workman
Mar 11, 2009·Gynecologic Oncology·Monica Prasad HayesLora Hedrick Ellenson
Jul 25, 2009·Nature Reviews. Cancer·Jeffrey A Engelman
Nov 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Haiyan WuJonathan M Backer
Feb 5, 2010·Virchows Archiv : an International Journal of Pathology·Silvia CarvalhoFernando Schmitt
Mar 10, 2010·Current Drug Targets·Walter Filgueira De Azevedo
Oct 26, 2010·Drug Discovery Today·Qingliang LiStephen H Bryant
Apr 28, 2011·Journal of Molecular Modeling·Ting RanYadong Chen
Nov 5, 2011·Nucleic Acids Research·Ivica LetunicPeer Bork
Feb 24, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xiaoyun LiaoShuji Ogino
Nov 20, 2012·Nucleic Acids Research·UNKNOWN UniProt Consortium
Mar 15, 2013·Molecular Biology and Evolution·Barry G Hall
Sep 17, 2013·Journal of Cellular Biochemistry·Shankar JayaramaBellur S Prabhakar
Nov 22, 2013·Nucleic Acids Research·UNKNOWN NCBI Resource Coordinators
May 28, 2014·Biochemical Pharmacology·Claudia FumarolaRoberta R Alfieri
Jun 15, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Muhan ChenLloyd C Trotman
Jun 15, 2014·Pharmacology & Therapeutics·Nadine Houédé, Philippe Pourquier
Jun 20, 2014·Computer Physics Communications·Wei JiangBenoît Roux

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