Exploring the Pi3ka and G Binding Sites by Homology Modeling And
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Exploring the Specificity of the PI3K Family Inhibitor LY294002
Exploring the specificity of the PI3K family inhibitor LY294002 Severine I Gharbi, Marketa J Zvelebil, Stephen J Shuttleworth, Tim Hancox, Nahid Saghir, John F Timms, Michael D Waterfield To cite this version: Severine I Gharbi, Marketa J Zvelebil, Stephen J Shuttleworth, Tim Hancox, Nahid Saghir, et al.. Exploring the specificity of the PI3K family inhibitor LY294002. Biochemical Journal, Portland Press, 2007, 404 (1), pp.15-21. 10.1042/BJ20061489. hal-00478676 HAL Id: hal-00478676 https://hal.archives-ouvertes.fr/hal-00478676 Submitted on 30 Apr 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Biochemical Journal Immediate Publication. Published on 15 Feb 2007 as manuscript BJ20061489 Title: Exploring the specificity of the PI3K family inhibitor LY294002 Authors: † ‡ ‡ Severine I. Gharbi*, Marketa J. Zvelebil , Stephen J. Shuttleworth , Tim Hancox , Nahid ‡ ‡¶ Saghir , John F. Timms*§ and Michael D. Waterfield* *Ludwig Institute for Cancer Research, Proteomics Unit, Cruciform Building, Gower † Street, London WCE1 6BT, UK. Ludwig Institute for Cancer Research, Bioinformatics ‡ Group, 91 Riding House Street, London W1W 7BS, UK. PIramed, 957 Buckingham Avenue, Slough, Berkshire, SL1 4NL, UK. §Transitional Research Laboratory, Institute of Women’s Health, University College London, Huntley Street, London, UK ¶ Corresponding Author: Professor M D Waterfield FRS, Email: [email protected]. -
LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced
Research Article LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway Tze Wei Poh1 and Shazib Pervaiz1,2,3 1Department of Physiology, 2Oncology Research Institute, National University Medical Institute, Faculty of Medicine, and 3Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore Abstract then recruits Akt/PKB to the membrane where it becomes The phosphoinositide 3-kinase (PI3K)-Akt pathway is consti- phosphorylated and thus activated by the phosphatidyl-dependent tutively active in many tumors, and inhibitors of this kinase-1. Akt/PKB has been implicated in the regulation of a variety prosurvival network, such as LY294002, have been shown to of signal transduction pathways that mediate gene transcription sensitize tumor cells to death stimuli. Here, we report a novel, (5–10), cell cycle events (11–15), cell proliferation (16–19), glycogen PI3K-independent mechanism of LY-mediated sensitization of and protein metabolism (20–22), angiogenesis (23, 24), DNA repair LNCaP prostate carcinoma cells to drug-induced apoptosis. (25, 26), and cell survival (27). Recent evidence strongly suggests Preincubation of tumor cells to LY294002 or its inactive that activated Akt/PKB not only contributes to oncogenic analogue LY303511 resulted in a significant increase in proliferative ability but also through phosphorylation of down- stream targets, such as Bad, confers resistance -
Small Molecule Inhibitors of the PI3-Kinase Family
Small Molecule Inhibitors of the PI3-Kinase Family Zachary A. Knight Contents 1 Introduction . 263 2 LY294002 . 265 3 Wortmannin . 267 4 p110d Inhibitors and the Selectivity Pocket . 268 5 p110b, DNA-PK, and ATM Inhibitors: A Shared Selectivity Mechanism? . 270 6 p110g Inhibitors . 272 7 Class I PI3-K Inhibitors . 273 8 Conclusions . 274 References . 274 Abstract The PI3-K family is one of the most intensely pursued classes of drug targets. This chapter reviews some of the chemical and structural features that determine the selectivity of PI3-K inhibitors, by focusing on a few key compounds that have been instrumental in guiding our understanding of how to design drugs against this family. 1 Introduction PI3-K was first identified in the late 1980s as an enzyme activity associated with immunoprecipitates of oncogenic tyrosine kinases (Kaplan et al. 1986; Whitman et al. 1985, 1988) and activated growth factor receptors (Kaplan et al. 1987; Ruderman et al. 1990). In 1992, PI3-K (p110a) was purified and cloned Z.A. Knight (*) The Rockefeller University, 1230 York Ave, New York, NY 10065, USA e-mail: [email protected] C. Rommel et al. (eds.). Phosphoinositide 3-kinase in Health and Disease, Volume 2 263 Current Topics in Microbiology and Immunology 347, DOI 10.1007/82_2010_44 # Springer‐Verlag Berlin Heidelberg 2010, published online: 7 May 2010 264 Z.A. Knight (Hiles et al. 1992), and it was shown to have sequence homology to VPS34, a yeast gene required for protein sorting (Robinson et al. 1988). This led to the rapid discovery of a family of 15 kinases, termed the PI3-K family, that share a conserved phosphoinositide kinase (PIK) domain but otherwise vary in their substrate speci- ficity, expression pattern, and modes of regulation. -
Structural Determinants of Isoform Selectivity in PI3K Inhibitors
Review Structural Determinants of Isoform Selectivity in PI3K Inhibitors Michelle S. Miller 1, Philip E. Thompson 2 and Sandra B. Gabelli 1,3,* 1 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; [email protected], 2 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia; [email protected] 3 Departments of Medicine, Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA * Correspondence [email protected]; Tel.: +410-614-4145 Received: 25 January 2019; Accepted: 21 February 2019; Published: 26 February 2019 Abstract: Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3K, PI3K, PI3K and PI3K have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues. Keywords: PIK3CA; isoform selectivity; p110; p85; phosphatidylinositol 3-kinase; PI3K; PI3K; PI3K; PI3K 1. Introduction With more than 500 members in the human kinome, kinases are the most common family of enzymatic drug targets for the treatment of cancer and other diseases [1]. -
Inhibitors of the PI3K/Akt/Mtor Pathway in Prostate Cancer Chemoprevention and Intervention
pharmaceutics Review Inhibitors of the PI3K/Akt/mTOR Pathway in Prostate Cancer Chemoprevention and Intervention Nazanin Momeni Roudsari 1, Naser-Aldin Lashgari 1 , Saeideh Momtaz 2,3,4 , Shaghayegh Abaft 1, Fatemeh Jamali 1, Pardis Safaiepour 1, Kiyana Narimisa 1, Gloria Jackson 5 , Anusha Bishayee 6, Nima Rezaei 7,8, Amir Hossein Abdolghaffari 1,2,3,4,* and Anupam Bishayee 5,* 1 Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran; [email protected] (N.M.R.); [email protected] (N.-A.L.); [email protected] (S.A.); [email protected] (F.J.); [email protected] (P.S.); [email protected] (K.N.) 2 Medicinal Plants Research Center, Institute of Medicinal Plants, Academic Center for Education, Culture and Research, Tehran 1417614411, Iran; [email protected] 3 Toxicology and Disease Group, Pharmaceutical Sciences Research Center, Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran 4 Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran 1417614411, Iran 5 Lake Erie Collage of Osteopathic Medicine, Bradenton, FL 34211, USA; [email protected] 6 Pine View School, Osprey, FL 34229, USA; [email protected] 7 Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Citation: Roudsari, N.M.; Lashgari, Tehran 1417614411, Iran; [email protected] 8 Department of Immunology, School of Medicine, Tehran University of Medical Sciences, N.-A.; Momtaz, S.; Abaft, S.; Jamali, F.; Tehran 1417614411, Iran Safaiepour, P.; Narimisa, K.; Jackson, * Correspondence: [email protected] (A.H.A.); G.; Bishayee, A.; Rezaei, N.; et al.