Second harmonic generation detection of Ras conformational changes and discovery of a small molecule binder.

Amino Acid Substitution Binding Sites Humans Mutation, Missense Nuclear Magnetic Resonance, Biomolecular Protein Kinase Inhibitors / chemistry Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
KRAS cancer second harmonic generation small G protein small molecule inhibitors

Journal

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876

Informations de publication

Date de publication:
27 08 2019
Historique:
pubmed: 11 8 2019
medline: 25 3 2020
entrez: 11 8 2019
Statut: ppublish

Résumé

Second harmonic generation (SHG) is an emergent biophysical method that sensitively measures real-time conformational change of biomolecules in the presence of biological ligands and small molecules. This study describes the successful implementation of SHG as a primary screening platform to identify fragment ligands to oncogenic Kirsten rat sarcoma (KRas). KRas is the most frequently mutated driver of pancreatic, colon, and lung cancers; however, there are few well-characterized small molecule ligands due to a lack of deep binding pockets. Using SHG, we identified a fragment binder to KRas

Identifiants

DOI: 10.1073/pnas.1905516116 PMID: 31399543 PMC: PMC6717309
pubmed: 31399543
pii: 1905516116
doi: 10.1073/pnas.1905516116
pmc: PMC6717309
doi:

Substances chimiques

KRAS protein, human 0
Protein Kinase Inhibitors 0
Proto-Oncogene Proteins p21(ras) EC 3.6.5.2

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

17290-17297

Subventions

Organisme : NCI NIH HHS
ID : R35 CA197709
Pays : United States
Organisme : NIH HHS
ID : S10 OD023482
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA108462
Pays : United States
Organisme : CCR NIH HHS
ID : HHSN261200800001C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200800001E
Pays : United States

Déclaration de conflit d'intérêts

Conflict of interest statement: E.D. and G.M. were previously employed at Biodesy, Inc. S.K. is an employee of Biodesy, Inc. A.D.M. is cofounder and Chief Scientific Officer of SilcsBio LLC. B.M. is an employee of Biodesy, Inc. and has equity grants in the company. J. Salafsky is the founder of Biodesy, Inc., where the research was performed. F.M. is a consultant for the following companies: Aduro Biotech; Amgen; Daiichi Ltd; Ideaya Biosciences; Kura Oncology; Leidos Biomedical Research, Inc.; PellePharm; Pfizer Inc.; PMV Pharma; Portola Pharmaceuticals; and Quanta Therapeutics. F.M. has received research grants from Daiichi Ltd and is a recipient of funded research from Gilead Sciences. F.M. is a consultant and cofounder for the following companies (with ownership interest, including stock options): BridgeBio; DNAtrix Inc.; Olema Pharmaceuticals, Inc.; and Quartz. F.M. is Scientific Director of the National Cancer Institute Ras Initiative at Frederick National Laboratory for Cancer Research/Leidos Biomedical Research, Inc.

Références

J Biomol Screen. 1999;4(2):67-73
pubmed: 10838414
Cell. 2003 Mar 7;112(5):685-95
pubmed: 12628188
J Chem Phys. 2006 Aug 21;125(7):074701
pubmed: 16942358
Phys Chem Chem Phys. 2007 Nov 14;9(42):5704-11
pubmed: 17960260
Curr Opin Struct Biol. 2009 Feb;19(1):56-61
pubmed: 19162472
Genes Cancer. 2011 Mar;2(3):359-72
pubmed: 21779505
Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5299-304
pubmed: 22431598
Angew Chem Int Ed Engl. 2012 Jun 18;51(25):6140-3
pubmed: 22566140
Cancer Cell. 2012 Dec 11;22(6):825-37
pubmed: 23238017
J Chem Inf Model. 2013 Dec 23;53(12):3384-98
pubmed: 24245913
Nature. 2013 Nov 28;503(7477):548-51
pubmed: 24256730
Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3401-6
pubmed: 24550516
J Comput Aided Mol Des. 2014 May;28(5):491-507
pubmed: 24610239
Cancer Cell. 2014 Mar 17;25(3):272-81
pubmed: 24651010
J Neuroinflammation. 2014 Jul 21;11:124
pubmed: 25043939
Nat Rev Drug Discov. 2014 Nov;13(11):828-51
pubmed: 25323927
J Chem Inf Model. 2015 Feb 23;55(2):407-20
pubmed: 25622696
Biophys J. 2015 Aug 18;109(4):806-15
pubmed: 26287632
J Biol Chem. 2015 Nov 13;290(46):27582-93
pubmed: 26396193
J Biol Chem. 2016 Jan 22;291(4):1703-18
pubmed: 26565026
Cancer Discov. 2016 Mar;6(3):316-29
pubmed: 26739882
Nat Rev Drug Discov. 2016 Nov;15(11):771-785
pubmed: 27469033
Anal Chem. 2016 Nov 1;88(21):10482-10489
pubmed: 27696827
Annu Rev Anal Chem (Palo Alto Calif). 2017 Jun 12;10(1):387-414
pubmed: 28301745
Cold Spring Harb Symp Quant Biol. 1988;53 Pt 2:849-54
pubmed: 2855502
J Biol Chem. 2017 Aug 4;292(31):12981-12993
pubmed: 28630043
Nat Commun. 2017 Oct 3;8(1):781
pubmed: 28974687
J Chem Inf Model. 2018 Feb 26;58(2):464-471
pubmed: 29320178
Cell. 2018 Jan 25;172(3):578-589.e17
pubmed: 29373830
Anal Biochem. 2018 May 1;548:44-52
pubmed: 29444450
Elife. 2018 Aug 02;7:
pubmed: 30074480
Methods Enzymol. 2018;610:167-190
pubmed: 30390798
Biochem J. 2019 Jan 31;476(2):365-374
pubmed: 30705085
Mol Cell Biol. 1986 Dec;6(12):4214-20
pubmed: 3540608
J Mol Biol. 1997 Nov 21;274(1):114-31
pubmed: 9398520
Nature. 1998 Jul 23;394(6691):337-43
pubmed: 9690470

Auteurs

Elizabeth Donohue (E)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
Biodesy, Inc., South San Francisco, CA 94080.

Sina Khorsand (S)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
Biodesy, Inc., South San Francisco, CA 94080.

Gabriel Mercado (G)

Biodesy, Inc., South San Francisco, CA 94080.

Kristen M Varney (KM)

Center for Biomolecular Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 21201.
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201.

Paul T Wilder (PT)

Center for Biomolecular Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 21201.
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201.

Wenbo Yu (W)

Center for Biomolecular Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 21201.
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201.

Alexander D MacKerell (AD)

Center for Biomolecular Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 21201.
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201.

Patrick Alexander (P)

National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702.

Que N Van (QN)

National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702.

Ben Moree (B)

Biodesy, Inc., South San Francisco, CA 94080.
ORCID: 0000-0002-8811-7400

Andrew G Stephen (AG)

National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702.

David J Weber (DJ)

Center for Biomolecular Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 21201.
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201.
ORCID: 0000-0002-8824-1110

Joshua Salafsky (J)

Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158 frank.mccormick@ucsf.edu joshua.salafsky@ucsf.edu.

Frank McCormick (F)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158; frank.mccormick@ucsf.edu joshua.salafsky@ucsf.edu.
National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Mutagenèse › Substitution d'acide aminé › Second harmonic generation detection of Ras...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › Second harmonic generation detection of Ras...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Second harmonic generation detection of Ras...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation faux-sens › Second harmonic generation detection of Ras...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Analyse spectrale › Spectroscopie par résonance magnétique › Résonance magnétique nucléaire biomoléculaire › Second harmonic generation detection of Ras...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Second harmonic generation detection of Ras...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes p21(ras) › Second harmonic generation detection of Ras...