Literature DB >> 24900593

Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.

Jeffrey M Axten1, Stuart P Romeril1, Arthur Shu1, Jeffrey Ralph1, Jesús R Medina1, Yanhong Feng1, William Hoi Hong Li1, Seth W Grant1, Dirk A Heerding1, Elisabeth Minthorn1, Thomas Mencken1, Nathan Gaul2, Aaron Goetz3, Thomas Stanley3, Annie M Hassell4, Robert T Gampe4, Charity Atkins1, Rakesh Kumar1.   

Abstract

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

Entities:  

Keywords:  PERK; UPR; fluorine interaction; kinase; lead optimization; structure−activity relationship

Year:  2013        PMID： 24900593      PMCID： PMC4027568          DOI： 10.1021/ml400228e

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  20 in total

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Authors:  David Ron; Peter Walter
Journal:  Nat Rev Mol Cell Biol       Date:  2007-07       Impact factor: 94.444

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Authors:  H P Harding; Y Zhang; D Ron
Journal:  Nature       Date:  1999-01-21       Impact factor: 49.962

3.  ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth.

Authors:  Meixia Bi; Christine Naczki; Marianne Koritzinsky; Diane Fels; Jaime Blais; Nianping Hu; Heather Harding; Isabelle Novoa; Mahesh Varia; James Raleigh; Donalyn Scheuner; Randal J Kaufman; John Bell; David Ron; Bradly G Wouters; Constantinos Koumenis
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4.  Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK).

Authors:  Jeffrey M Axten; Jesús R Medina; Yanhong Feng; Arthur Shu; Stuart P Romeril; Seth W Grant; William Hoi Hong Li; Dirk A Heerding; Elisabeth Minthorn; Thomas Mencken; Charity Atkins; Qi Liu; Sridhar Rabindran; Rakesh Kumar; Xuan Hong; Aaron Goetz; Thomas Stanley; J David Taylor; Scott D Sigethy; Ginger H Tomberlin; Annie M Hassell; Kirsten M Kahler; Lisa M Shewchuk; Robert T Gampe
Journal:  J Med Chem       Date:  2012-08-08       Impact factor: 7.446

5.  The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas.

Authors:  Peichuan Zhang; Barbara McGrath; Sheng'ai Li; Ami Frank; Frank Zambito; Jamie Reinert; Maureen Gannon; Kun Ma; Kelly McNaughton; Douglas R Cavener
Journal:  Mol Cell Biol       Date:  2002-06       Impact factor: 4.272

6.  Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress.

Authors:  Jaime D Blais; Christina L Addison; Robert Edge; Theresa Falls; Huijun Zhao; Kishore Wary; Costas Koumenis; Heather P Harding; David Ron; Martin Holcik; John C Bell
Journal:  Mol Cell Biol       Date:  2006-10-09       Impact factor: 4.272

7.  Transcriptional regulation of VEGF-A by the unfolded protein response pathway.

Authors:  Rajarshi Ghosh; Kathryn L Lipson; Karen E Sargent; Arthur M Mercurio; Joan S Hunt; David Ron; Fumihiko Urano
Journal:  PLoS One       Date:  2010-03-08       Impact factor: 3.240

8.  Transcriptional and post-transcriptional regulation of proangiogenic factors by the unfolded protein response.

Authors:  Ethel R Pereira; Nan Liao; Geoff A Neale; Linda M Hendershot
Journal:  PLoS One       Date:  2010-09-02       Impact factor: 3.240

9.  PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis.

Authors:  Yan Gao; Daniel J Sartori; Changhong Li; Qian-Chun Yu; Jake A Kushner; M Celeste Simon; J Alan Diehl
Journal:  Mol Cell Biol       Date:  2012-10-15       Impact factor: 4.272

Review 10.  Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities.

Authors:  Inki Kim; Wenjie Xu; John C Reed
Journal:  Nat Rev Drug Discov       Date:  2008-12       Impact factor: 84.694
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  75 in total

1.  When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157.

Authors:  Diego Rojas-Rivera; Tinneke Delvaeye; Ria Roelandt; Wim Nerinckx; Koen Augustyns; Peter Vandenabeele; Mathieu J M Bertrand
Journal:  Cell Death Differ       Date:  2017-04-28       Impact factor: 15.828

Review 2.  Biology and Pathobiology of TDP-43 and Emergent Therapeutic Strategies.

Authors:  Lin Guo; James Shorter
Journal:  Cold Spring Harb Perspect Med       Date:  2017-09-01       Impact factor: 6.915

Review 3.  Cellular signaling pathways modulated by low-intensity extracorporeal shock wave therapy.

Authors:  Tianshu Liu; Alan W Shindel; Guiting Lin; Tom F Lue
Journal:  Int J Impot Res       Date:  2019-01-22       Impact factor: 2.896

Review 4.  Small molecule strategies to harness the unfolded protein response: where do we go from here?

Authors:  Julia M D Grandjean; R Luke Wiseman
Journal:  J Biol Chem       Date:  2020-09-04       Impact factor: 5.157

Review 5.  Role of eIF2α Kinases in Translational Control and Adaptation to Cellular Stress.

Authors:  Ronald C Wek
Journal:  Cold Spring Harb Perspect Biol       Date:  2018-07-02       Impact factor: 10.005

Review 6.  Therapeutic Opportunities in Eukaryotic Translation.

Authors:  Jennifer Chu; Jerry Pelletier
Journal:  Cold Spring Harb Perspect Biol       Date:  2018-06-01       Impact factor: 10.005

7.  Excessive ER-phagy mediated by the autophagy receptor FAM134B results in ER stress, the unfolded protein response, and cell death in HeLa cells.

Authors:  Yangjie Liao; Bo Duan; Yufei Zhang; Xinmin Zhang; Bin Xia
Journal:  J Biol Chem       Date:  2019-11-20       Impact factor: 5.157

8.  Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes.

Authors:  Zachary S Nevin; Daniel C Factor; Robert T Karl; Panagiotis Douvaras; Jeremy Laukka; Martha S Windrem; Steven A Goldman; Valentina Fossati; Grace M Hobson; Paul J Tesar
Journal:  Am J Hum Genet       Date:  2017-03-30       Impact factor: 11.025

Review 9.  Natural products as modulators of eukaryotic protein secretion.

Authors:  Hendrik Luesch; Ville O Paavilainen
Journal:  Nat Prod Rep       Date:  2020-02-18       Impact factor: 13.423

Review 10.  Chemical Biology Framework to Illuminate Proteostasis.

Authors:  Rebecca M Sebastian; Matthew D Shoulders
Journal:  Annu Rev Biochem       Date:  2020-02-25       Impact factor: 23.643
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