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

Title: Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5- d ]pyrrolo[2,3- b ]pyridine Inhibitors

Abstract

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
+ Show Author Affiliations
  1. Bristol-Myers Squibb Research and Development, Princeton, NJ (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1397312
Resource Type:
Accepted Manuscript
Journal Name:
ACS Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 6; Journal Issue: 8; Journal ID: ISSN 1948-5875
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Kinase; Janus kinase 2 (JAK2); thiazole; myeloproliferative neoplasms; structure-based drug design (SBDD)

Citation Formats

Hart, Amy C., Schroeder, Gretchen M., Wan, Honghe, Grebinski, James, Inghrim, Jennifer, Kempson, James, Guo, Junqing, Pitts, William J., Tokarski, John S., Sack, John S., Khan, Javed A., Lippy, Jonathan, Lorenzi, Matthew V., You, Dan, McDevitt, Theresa, Vuppugalla, Ragini, Zhang, Yueping, Lombardo, Louis J., Trainor, George L., and Purandare, Ashok V. Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5- d ]pyrrolo[2,3- b ]pyridine Inhibitors. United States: N. p., 2015. Web. doi:10.1021/acsmedchemlett.5b00225.
Copy to clipboard
Hart, Amy C., Schroeder, Gretchen M., Wan, Honghe, Grebinski, James, Inghrim, Jennifer, Kempson, James, Guo, Junqing, Pitts, William J., Tokarski, John S., Sack, John S., Khan, Javed A., Lippy, Jonathan, Lorenzi, Matthew V., You, Dan, McDevitt, Theresa, Vuppugalla, Ragini, Zhang, Yueping, Lombardo, Louis J., Trainor, George L., & Purandare, Ashok V. Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5- d ]pyrrolo[2,3- b ]pyridine Inhibitors. United States. https://doi.org/10.1021/acsmedchemlett.5b00225
Copy to clipboard
Hart, Amy C., Schroeder, Gretchen M., Wan, Honghe, Grebinski, James, Inghrim, Jennifer, Kempson, James, Guo, Junqing, Pitts, William J., Tokarski, John S., Sack, John S., Khan, Javed A., Lippy, Jonathan, Lorenzi, Matthew V., You, Dan, McDevitt, Theresa, Vuppugalla, Ragini, Zhang, Yueping, Lombardo, Louis J., Trainor, George L., and Purandare, Ashok V. Tue . "Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5- d ]pyrrolo[2,3- b ]pyridine Inhibitors". United States. https://doi.org/10.1021/acsmedchemlett.5b00225. https://www.osti.gov/servlets/purl/1397312.
Copy to clipboard
@article{osti_1397312,
title = {Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5- d ]pyrrolo[2,3- b ]pyridine Inhibitors},
author = {Hart, Amy C. and Schroeder, Gretchen M. and Wan, Honghe and Grebinski, James and Inghrim, Jennifer and Kempson, James and Guo, Junqing and Pitts, William J. and Tokarski, John S. and Sack, John S. and Khan, Javed A. and Lippy, Jonathan and Lorenzi, Matthew V. and You, Dan and McDevitt, Theresa and Vuppugalla, Ragini and Zhang, Yueping and Lombardo, Louis J. and Trainor, George L. and Purandare, Ashok V.},
abstractNote = {Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.},
doi = {10.1021/acsmedchemlett.5b00225},
journal = {ACS Medicinal Chemistry Letters},
number = 8,
volume = 6,
place = {United States},
year = {Tue Jul 14 00:00:00 EDT 2015},
month = {Tue Jul 14 00:00:00 EDT 2015}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1021/acsmedchemlett.5b00225
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 10 works
Citation information provided by
Web of Science

Figures / Tables:

Figure 1 Figure 1: Hit to lead SAR.
All figures and tables (9 total)
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:

A Role for JAK2 Mutations in Myeloproliferative Diseases
journal, February 2008

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders
journal, March 2005

A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
journal, April 2005

  • Kralovics, Robert; Passamonti, Francesco; Buser, Andreas S.
  • New England Journal of Medicine, Vol. 352, Issue 17
  • DOI: 10.1056/NEJMoa051113

A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera
journal, March 2005

  • James, Chloé; Ugo, Valérie; Le Couédic, Jean-Pierre
  • Nature, Vol. 434, Issue 7037
  • DOI: 10.1038/nature03546

Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis
journal, December 2013

Synthesis, initial SAR and biological evaluation of 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine derived inhibitors of IκB kinase
journal, May 2009

  • Kempson, James; Guo, Junqing; Das, Jagabandhu
  • Bioorganic & Medicinal Chemistry Letters, Vol. 19, Issue 10
  • DOI: 10.1016/j.bmcl.2009.03.159

Investigational Janus kinase inhibitors
journal, February 2013

A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design
journal, March 2015

  • Beno, Brett R.; Yeung, Kap-Sun; Bartberger, Michael D.
  • Journal of Medicinal Chemistry, Vol. 58, Issue 11
  • DOI: 10.1021/jm501853m

A small molecule–kinase interaction map for clinical kinase inhibitors
journal, February 2005

  • Fabian, Miles A.; Biggs, William H.; Treiber, Daniel K.
  • Nature Biotechnology, Vol. 23, Issue 3
  • DOI: 10.1038/nbt1068

Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms
journal, July 2015

    Sort by:
    [ × clear filter / sort ]

    Works referencing / citing this record:

    Understanding the structural features of JAK2 inhibitors: a combined 3D-QSAR, DFT and molecular dynamics study
    journal, January 2019

    • Babu, Sathya; Nagarajan, Santhosh Kumar; Madhavan, Thirumurthy
    • Molecular Diversity, Vol. 23, Issue 4
    • DOI: 10.1007/s11030-018-09913-4
      Sort by:
      [ × clear filter / sort ]

      Figures / Tables found in this record:

      Figure 1 (p. 1)figure
      Figure 2 (p. 2)figure
      Scheme 1 (p. 2)figure
      Table 1 (p. 2)table
      Scheme 2 (p. 3)figure
      Table 2 (p. 3)table
      Figure 3 (p. 4)figure
      Table 3 (p. 4)table
      Table 4 (p. 4)table
        [ × clear filter / sort ]
        Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.

        Similar Records in DOE PAGES and OSTI.GOV collections: