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Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70.

Publication ,  Journal Article
Howe, MK; Bodoor, K; Carlson, DA; Hughes, PF; Alwarawrah, Y; Loiselle, DR; Jaeger, AM; Darr, DB; Jordan, JL; Hunter, LM; Molzberger, ET ...
Published in: Chem Biol
December 18, 2014

Inducible Hsp70 (Hsp70i) is overexpressed in a wide spectrum of human tumors, and its expression correlates with metastasis, poor outcomes, and resistance to chemotherapy in patients. Identification of small-molecule inhibitors selective for Hsp70i could provide new therapeutic tools for cancer treatment. In this work, we used fluorescence-linked enzyme chemoproteomic strategy (FLECS) to identify HS-72, an allosteric inhibitor selective for Hsp70i. HS-72 displays the hallmarks of Hsp70 inhibition in cells, promoting substrate protein degradation and growth inhibition. Importantly, HS-72 is selective for Hsp70i over the closely related constitutively active Hsc70. Studies with purified protein show HS-72 acts as an allosteric inhibitor, reducing ATP affinity. In vivo HS-72 is well-tolerated, showing bioavailability and efficacy, inhibiting tumor growth and promoting survival in a HER2+ model of breast cancer. The HS-72 scaffold is amenable to resynthesis and iteration, suggesting an ideal starting point for a new generation of anticancer therapeutics targeting Hsp70i.

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Published In

Chem Biol

DOI

EISSN

1879-1301

Publication Date

December 18, 2014

Volume

21

Issue

12

Start / End Page

1648 / 1659

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Protein Structure, Tertiary
  • Protein Aggregates
  • Piperidines
  • Permeability
  • Organic Chemistry
  • Nipecotic Acids
  • Models, Molecular
  • Mice
  • Humans
 

Citation

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Howe, M. K., Bodoor, K., Carlson, D. A., Hughes, P. F., Alwarawrah, Y., Loiselle, D. R., … Haystead, T. A. J. (2014). Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70. Chem Biol, 21(12), 1648–1659. https://doi.org/10.1016/j.chembiol.2014.10.016
Howe, Matthew K., Khaldon Bodoor, David A. Carlson, Philip F. Hughes, Yazan Alwarawrah, David R. Loiselle, Alex M. Jaeger, et al. “Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70.Chem Biol 21, no. 12 (December 18, 2014): 1648–59. https://doi.org/10.1016/j.chembiol.2014.10.016.
Howe MK, Bodoor K, Carlson DA, Hughes PF, Alwarawrah Y, Loiselle DR, et al. Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70. Chem Biol. 2014 Dec 18;21(12):1648–59.
Howe, Matthew K., et al. “Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70.Chem Biol, vol. 21, no. 12, Dec. 2014, pp. 1648–59. Pubmed, doi:10.1016/j.chembiol.2014.10.016.
Howe MK, Bodoor K, Carlson DA, Hughes PF, Alwarawrah Y, Loiselle DR, Jaeger AM, Darr DB, Jordan JL, Hunter LM, Molzberger ET, Gobillot TA, Thiele DJ, Brodsky JL, Spector NL, Haystead TAJ. Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70. Chem Biol. 2014 Dec 18;21(12):1648–1659.

Published In

Chem Biol

DOI

EISSN

1879-1301

Publication Date

December 18, 2014

Volume

21

Issue

12

Start / End Page

1648 / 1659

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Protein Structure, Tertiary
  • Protein Aggregates
  • Piperidines
  • Permeability
  • Organic Chemistry
  • Nipecotic Acids
  • Models, Molecular
  • Mice
  • Humans