Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Drugging an undruggable pocket on KRAS

Abstract

The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be “undruggable,” between switch I and II on RAS; 1 is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactivemore » forms of KRAS« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1] more »;  [1];  [1];  [3];  [1];  [1];  [2];  [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [4];  [1];  [3];  [1];  [4]; ORCiD logo [1] « less
+ Show Author Affiliations
  1. Boehringer Ingelheim Regional Center Vienna GmbH & Co KG (Austria)
  2. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
  3. Boehringer Ingelheim Pharma GmbH & Co KG (Germany)
  4. Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Vanderbilt Univ., Nashville, TN (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); National Cancer Institute (NCI); Lustgarten Foundation for Pancreatic Cancer Research; Austrian Forschungsförderungsgesellschaft (FFG); USDOE Office of Science (SC)
OSTI Identifier:
1593440
Grant/Contract Number:  
P50A095103; RC2CA148375; 854341; 861507; AC02-06CH11357; P30CA68485
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 32; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; KRAS; NMR; oncology; structure-based drug design; fragment-based drug design

Citation Formats

Kessler, Dirk, Gmachl, Michael, Mantoulidis, Andreas, Martin, Laetitia J., Zoephel, Andreas, Mayer, Moriz, Gollner, Andreas, Covini, David, Fischer, Silke, Gerstberger, Thomas, Gmaschitz, Teresa, Goodwin, Craig, Greb, Peter, Häring, Daniela, Hela, Wolfgang, Hoffmann, Johann, Karolyi-Oezguer, Jale, Knesl, Petr, Kornigg, Stefan, Koegl, Manfred, Kousek, Roland, Lamarre, Lyne, Moser, Franziska, Munico-Martinez, Silvia, Peinsipp, Christoph, Phan, Jason, Rinnenthal, Jörg, Sai, Jiqing, Salamon, Christian, Scherbantin, Yvonne, Schipany, Katharina, Schnitzer, Renate, Schrenk, Andreas, Sharps, Bernadette, Siszler, Gabriella, Sun, Qi, Waterson, Alex, Wolkerstorfer, Bernhard, Zeeb, Markus, Pearson, Mark, Fesik, Stephen W., and McConnell, Darryl B. Drugging an undruggable pocket on KRAS. United States: N. p., 2019. Web. doi:10.1073/pnas.1904529116.
Copy to clipboard
Kessler, Dirk, Gmachl, Michael, Mantoulidis, Andreas, Martin, Laetitia J., Zoephel, Andreas, Mayer, Moriz, Gollner, Andreas, Covini, David, Fischer, Silke, Gerstberger, Thomas, Gmaschitz, Teresa, Goodwin, Craig, Greb, Peter, Häring, Daniela, Hela, Wolfgang, Hoffmann, Johann, Karolyi-Oezguer, Jale, Knesl, Petr, Kornigg, Stefan, Koegl, Manfred, Kousek, Roland, Lamarre, Lyne, Moser, Franziska, Munico-Martinez, Silvia, Peinsipp, Christoph, Phan, Jason, Rinnenthal, Jörg, Sai, Jiqing, Salamon, Christian, Scherbantin, Yvonne, Schipany, Katharina, Schnitzer, Renate, Schrenk, Andreas, Sharps, Bernadette, Siszler, Gabriella, Sun, Qi, Waterson, Alex, Wolkerstorfer, Bernhard, Zeeb, Markus, Pearson, Mark, Fesik, Stephen W., & McConnell, Darryl B. Drugging an undruggable pocket on KRAS. United States. https://doi.org/10.1073/pnas.1904529116
Copy to clipboard
Kessler, Dirk, Gmachl, Michael, Mantoulidis, Andreas, Martin, Laetitia J., Zoephel, Andreas, Mayer, Moriz, Gollner, Andreas, Covini, David, Fischer, Silke, Gerstberger, Thomas, Gmaschitz, Teresa, Goodwin, Craig, Greb, Peter, Häring, Daniela, Hela, Wolfgang, Hoffmann, Johann, Karolyi-Oezguer, Jale, Knesl, Petr, Kornigg, Stefan, Koegl, Manfred, Kousek, Roland, Lamarre, Lyne, Moser, Franziska, Munico-Martinez, Silvia, Peinsipp, Christoph, Phan, Jason, Rinnenthal, Jörg, Sai, Jiqing, Salamon, Christian, Scherbantin, Yvonne, Schipany, Katharina, Schnitzer, Renate, Schrenk, Andreas, Sharps, Bernadette, Siszler, Gabriella, Sun, Qi, Waterson, Alex, Wolkerstorfer, Bernhard, Zeeb, Markus, Pearson, Mark, Fesik, Stephen W., and McConnell, Darryl B. Mon . "Drugging an undruggable pocket on KRAS". United States. https://doi.org/10.1073/pnas.1904529116. https://www.osti.gov/servlets/purl/1593440.
Copy to clipboard
@article{osti_1593440,
title = {Drugging an undruggable pocket on KRAS},
author = {Kessler, Dirk and Gmachl, Michael and Mantoulidis, Andreas and Martin, Laetitia J. and Zoephel, Andreas and Mayer, Moriz and Gollner, Andreas and Covini, David and Fischer, Silke and Gerstberger, Thomas and Gmaschitz, Teresa and Goodwin, Craig and Greb, Peter and Häring, Daniela and Hela, Wolfgang and Hoffmann, Johann and Karolyi-Oezguer, Jale and Knesl, Petr and Kornigg, Stefan and Koegl, Manfred and Kousek, Roland and Lamarre, Lyne and Moser, Franziska and Munico-Martinez, Silvia and Peinsipp, Christoph and Phan, Jason and Rinnenthal, Jörg and Sai, Jiqing and Salamon, Christian and Scherbantin, Yvonne and Schipany, Katharina and Schnitzer, Renate and Schrenk, Andreas and Sharps, Bernadette and Siszler, Gabriella and Sun, Qi and Waterson, Alex and Wolkerstorfer, Bernhard and Zeeb, Markus and Pearson, Mark and Fesik, Stephen W. and McConnell, Darryl B.},
abstractNote = {The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be “undruggable,” between switch I and II on RAS; 1 is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS},
doi = {10.1073/pnas.1904529116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 32,
volume = 116,
place = {United States},
year = {Mon Jul 22 00:00:00 EDT 2019},
month = {Mon Jul 22 00:00:00 EDT 2019}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1073/pnas.1904529116
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 179 works
Citation information provided by
Web of Science
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment
journal, August 2018

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
journal, October 2012

  • Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.
  • Nature, Vol. 491, Issue 7424
  • DOI: 10.1038/nature11547

Structure-based Mutagenesis Reveals Distinct Functions for Ras Switch 1 and Switch 2 in Sos-catalyzed Guanine Nucleotide Exchange
journal, May 2001

  • Hall, Brian E.; Yang, Shao Song; Boriack-Sjodin, P. Ann
  • Journal of Biological Chemistry, Vol. 276, Issue 29
  • DOI: 10.1074/jbc.M101727200

Three-dimensional structure of the Ras-interacting domain of RalGDS
journal, August 1997

  • Huang, Lan; Weng, Xiangwei; Hofer, Franz
  • Natural Structural Biology, Vol. 4, Issue 8
  • DOI: 10.1038/nsb0897-609

Discovering High-Affinity Ligands for Proteins: SAR by NMR
journal, November 1996

New structural and functional insight into the regulation of Ras
journal, October 2016

Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds
journal, January 2019

  • Cruz-Migoni, Abimael; Canning, Peter; Quevedo, Camilo E.
  • Proceedings of the National Academy of Sciences, Vol. 116, Issue 7
  • DOI: 10.1073/pnas.1811360116

Structural analysis of the GAP-related domain from neurofibromin and its implications
journal, August 1998

BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition
journal, September 2015

Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
journal, July 2016

  • Ostrem, Jonathan M. L.; Shokat, Kevan M.
  • Nature Reviews Drug Discovery, Vol. 15, Issue 11
  • DOI: 10.1038/nrd.2016.139

A Comprehensive Survey of Ras Mutations in Cancer
journal, May 2012

MicroScale Thermophoresis: Interaction analysis and beyond
journal, December 2014

High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling
journal, May 2018

Structural Evidence for Feedback Activation by Ras·GTP of the Ras-Specific Nucleotide Exchange Factor SOS
journal, March 2003

Dynamic properties of the Ras switch I region and its importance for binding to effectors
journal, April 2001

  • Spoerner, M.; Herrmann, C.; Vetter, I. R.
  • Proceedings of the National Academy of Sciences, Vol. 98, Issue 9
  • DOI: 10.1073/pnas.081441398

Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer
journal, December 2009

  • Neumann, Jens; Zeindl-Eberhart, Evelyn; Kirchner, Thomas
  • Pathology - Research and Practice, Vol. 205, Issue 12
  • DOI: 10.1016/j.prp.2009.07.010

Group Epitope Mapping by Saturation Transfer Difference NMR To Identify Segments of a Ligand in Direct Contact with a Protein Receptor
journal, June 2001

  • Mayer, Moriz; Meyer, Bernd
  • Journal of the American Chemical Society, Vol. 123, Issue 25
  • DOI: 10.1021/ja0100120

Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E Melanomas
journal, November 2012

Evaluation of Solvent Accessibility Epitopes for Different Dehydrogenase Inhibitors
journal, September 2008

  • Ludwig, Christian; Michiels, Paulus J. A.; Lodi, Alessia
  • ChemMedChem, Vol. 3, Issue 9
  • DOI: 10.1002/cmdc.200800110

CASTp 3.0: computed atlas of surface topography of proteins
journal, June 2018

  • Tian, Wei; Chen, Chang; Lei, Xue
  • Nucleic Acids Research, Vol. 46, Issue W1
  • DOI: 10.1093/nar/gky473

A decade of fragment-based drug design: strategic advances and lessons learned
journal, February 2007

  • Hajduk, Philip J.; Greer, Jonathan
  • Nature Reviews Drug Discovery, Vol. 6, Issue 3
  • DOI: 10.1038/nrd2220

Design and Characterization of Libraries of Molecular Fragments for Use in NMR Screening against Protein Targets
journal, November 2004

  • Baurin, Nicolas; Aboul-Ela, Fareed; Barril, Xavier
  • Journal of Chemical Information and Computer Sciences, Vol. 44, Issue 6
  • DOI: 10.1021/ci049806z

FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma
journal, May 2005

  • Jebar, Adel H.; Hurst, Carolyn D.; Tomlinson, Darren C.
  • Oncogene, Vol. 24, Issue 33
  • DOI: 10.1038/sj.onc.1208705

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor
journal, January 2018

Fragment-based screening using X-ray crystallography and NMR spectroscopy
journal, October 2007

  • Jhoti, Harren; Cleasby, Anne; Verdonk, Marcel
  • Current Opinion in Chemical Biology, Vol. 11, Issue 5
  • DOI: 10.1016/j.cbpa.2007.07.010

Structural insights into phosphoinositide 3-kinase catalysis and signalling
journal, November 1999

  • Walker, Edward H.; Perisic, Olga; Ried, Christian
  • Nature, Vol. 402, Issue 6759
  • DOI: 10.1038/46319

Human RAS Superfamily Proteins and Related GTPases
journal, September 2004

Sos1 disruption impairs cellular proliferation and viability through an increase in mitochondrial oxidative stress in primary MEFs
journal, May 2016

  • Liceras-Boillos, P.; García-Navas, R.; Ginel-Picardo, A.
  • Oncogene, Vol. 35, Issue 50
  • DOI: 10.1038/onc.2016.169

Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation
journal, May 2012

  • Sun, Qi; Burke, Jason P.; Phan, Jason
  • Angewandte Chemie International Edition, Vol. 51, Issue 25
  • DOI: 10.1002/anie.201201358

H-ras gene mutations in salivary gland mucoepidermoid carcinomas
journal, February 2000

The structural basis of the activation of Ras by Sos
journal, July 1998

  • Boriack-Sjodin, P. Ann; Margarit, S. Mariana; Bar-Sagi, Dafna
  • Nature, Vol. 394, Issue 6691
  • DOI: 10.1038/28548

Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD
journal, March 2015

Partial functional overlap of the three ras genes in mouse embryonic development
journal, December 2007

The Guanine Nucleotide-Binding Switch in Three Dimensions
journal, November 2001

Luminescent oxygen channeling immunoassay: measurement of particle binding kinetics by chemiluminescence.
journal, June 1994

  • Ullman, E. F.; Kirakossian, H.; Singh, S.
  • Proceedings of the National Academy of Sciences, Vol. 91, Issue 12
  • DOI: 10.1073/pnas.91.12.5426

Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity
journal, March 2012

  • Maurer, T.; Garrenton, L. S.; Oh, A.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 14
  • DOI: 10.1073/pnas.1116510109

Implications of NRAS mutations in AML: a study of 2502 patients
journal, May 2006

Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation
journal, May 2012

Frequency and Type of KRAS Mutations in Routine Diagnostic Analysis of Metastatic Colorectal Cancer
journal, October 2009

  • Neumann, J.; Zeindl-Eberhart, E.; Kirchner, T.
  • Zeitschrift für Gastroenterologie, Vol. 47, Issue 10
  • DOI: 10.1055/s-0029-1242277

High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling
journal, May 2018

Fragment-based screening using X-ray crystallography and NMR spectroscopy
journal, October 2007

  • Jhoti, Harren; Cleasby, Anne; Verdonk, Marcel
  • Current Opinion in Chemical Biology, Vol. 11, Issue 5
  • DOI: 10.1016/j.cbpa.2007.07.010

BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition
journal, September 2015

Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E Melanomas
journal, November 2012

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor
journal, January 2018

MicroScale Thermophoresis: Interaction analysis and beyond
journal, December 2014

Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer
journal, December 2009

  • Neumann, Jens; Zeindl-Eberhart, Evelyn; Kirchner, Thomas
  • Pathology - Research and Practice, Vol. 205, Issue 12
  • DOI: 10.1016/j.prp.2009.07.010

Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD
journal, March 2015

Design and Characterization of Libraries of Molecular Fragments for Use in NMR Screening against Protein Targets
journal, November 2004

  • Baurin, Nicolas; Aboul-Ela, Fareed; Barril, Xavier
  • Journal of Chemical Information and Computer Sciences, Vol. 44, Issue 6
  • DOI: 10.1021/ci049806z

The structural basis of the activation of Ras by Sos
journal, July 1998

  • Boriack-Sjodin, P. Ann; Margarit, S. Mariana; Bar-Sagi, Dafna
  • Nature, Vol. 394, Issue 6691
  • DOI: 10.1038/28548

Structural insights into phosphoinositide 3-kinase catalysis and signalling
journal, November 1999

  • Walker, Edward H.; Perisic, Olga; Ried, Christian
  • Nature, Vol. 402, Issue 6759
  • DOI: 10.1038/46319

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
journal, October 2012

  • Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.
  • Nature, Vol. 491, Issue 7424
  • DOI: 10.1038/nature11547

A decade of fragment-based drug design: strategic advances and lessons learned
journal, February 2007

  • Hajduk, Philip J.; Greer, Jonathan
  • Nature Reviews Drug Discovery, Vol. 6, Issue 3
  • DOI: 10.1038/nrd2220

Sos1 disruption impairs cellular proliferation and viability through an increase in mitochondrial oxidative stress in primary MEFs
journal, May 2016

  • Liceras-Boillos, P.; García-Navas, R.; Ginel-Picardo, A.
  • Oncogene, Vol. 35, Issue 50
  • DOI: 10.1038/onc.2016.169

FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma
journal, May 2005

  • Jebar, Adel H.; Hurst, Carolyn D.; Tomlinson, Darren C.
  • Oncogene, Vol. 24, Issue 33
  • DOI: 10.1038/sj.onc.1208705

Dynamic properties of the Ras switch I region and its importance for binding to effectors
journal, April 2001

  • Spoerner, M.; Herrmann, C.; Vetter, I. R.
  • Proceedings of the National Academy of Sciences, Vol. 98, Issue 9
  • DOI: 10.1073/pnas.081441398

Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity
journal, March 2012

  • Maurer, T.; Garrenton, L. S.; Oh, A.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 14
  • DOI: 10.1073/pnas.1116510109

Luminescent oxygen channeling immunoassay: measurement of particle binding kinetics by chemiluminescence.
journal, June 1994

  • Ullman, E. F.; Kirakossian, H.; Singh, S.
  • Proceedings of the National Academy of Sciences, Vol. 91, Issue 12
  • DOI: 10.1073/pnas.91.12.5426

Structural analysis of the GAP-related domain from neurofibromin and its implications
journal, August 1998

CASTp 3.0: computed atlas of surface topography of proteins
journal, June 2018

  • Tian, Wei; Chen, Chang; Lei, Xue
  • Nucleic Acids Research, Vol. 46, Issue W1
  • DOI: 10.1093/nar/gky473

Fragment approaches in structure-based drug discovery
journal, April 2008

The Guanine Nucleotide-Binding Switch in Three Dimensions
journal, November 2001

GAP into the Breach
journal, July 1997

Human RAS Superfamily Proteins and Related GTPases
journal, September 2004

Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations
journal, June 2015

BRAF/NRAS Mutation Frequencies Among Primary Tumors and Metastases in Patients With Melanoma
journal, July 2012

  • Colombino, Maria; Capone, Mariaelena; Lissia, Amelia
  • Journal of Clinical Oncology, Vol. 30, Issue 20
  • DOI: 10.1200/jco.2011.41.2452
    Sort by:
    [ × clear filter / sort ]

    Works referencing / citing this record:

    Inhibition of K-Ras4B-plasma membrane association with a membrane microdomain-targeting peptide
    journal, January 2020

    • Li, Fang-Yi; Zhang, Zhen-Feng; Voss, Stephanie
    • Chemical Science, Vol. 11, Issue 3
    • DOI: 10.1039/c9sc04726c

    Therapeutic targeting of protein S-acylation for the treatment of disease
    journal, December 2019

    • Fraser, Niall J.; Howie, Jacqueline; Wypijewski, Krzysztof J.
    • Biochemical Society Transactions, Vol. 48, Issue 1
    • DOI: 10.1042/bst20190707

    The small molecule BI-2852 induces a nonfunctional dimer of KRAS
    journal, February 2020

    • Tran, Timothy H.; Alexander, Patrick; Dharmaiah, Srisathiyanarayanan
    • Proceedings of the National Academy of Sciences, Vol. 117, Issue 7
    • DOI: 10.1073/pnas.1918164117

    Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics
    journal, November 2019

    Exploiting RAS Nucleotide Cycling as a Strategy for Drugging RAS-Driven Cancers
    journal, December 2019

    • Mattox, Tyler E.; Chen, Xi; Maxuitenko, Yulia Y.
    • International Journal of Molecular Sciences, Vol. 21, Issue 1
    • DOI: 10.3390/ijms21010141

    Defining and Targeting Adaptations to Oncogenic KRASG12C Inhibition Using Quantitative Temporal Proteomics
    journal, March 2020

    Targeting Endogenous K-RAS for Degradation Through the Affinity-Directed Protein Missile System
    journal, January 2019

    • Röth, Sascha; Macartney, Thomas J.; Konopacka, Agnieszka
    • SSRN Electronic Journal
    • DOI: 10.2139/ssrn.3485244

    The current understanding of KRAS protein structure and dynamics
    journal, January 2020

    A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
    journal, June 2020

    The small molecule BI-2852 induces a nonfunctional dimer of KRAS
    journal, February 2020

    • Tran, Timothy H.; Alexander, Patrick; Dharmaiah, Srisathiyanarayanan
    • Proceedings of the National Academy of Sciences, Vol. 117, Issue 7
    • DOI: 10.1073/pnas.1918164117

    Reply to Tran et al.: Dimeric KRAS protein–protein interaction stabilizers
    journal, February 2020

    • Kessler, Dirk; Gollner, Andreas; Gmachl, Michael
    • Proceedings of the National Academy of Sciences, Vol. 117, Issue 7
    • DOI: 10.1073/pnas.1921236117

    RAS Nanoclusters: Dynamic Signaling Platforms Amenable to Therapeutic Intervention
    journal, March 2021

    • Van, Que N.; Prakash, Priyanka; Shrestha, Rebika
    • Biomolecules, Vol. 11, Issue 3
    • DOI: 10.3390/biom11030377

    Insights into Structures and Dynamics of Flavivirus Proteases from NMR Studies
    journal, April 2020

    • Li, Qingxin; Kang, CongBao
    • International Journal of Molecular Sciences, Vol. 21, Issue 7
    • DOI: 10.3390/ijms21072527
      Sort by:
      [ × clear filter / sort ]

      Similar Records in DOE PAGES and OSTI.GOV collections: