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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • December 18, 2014

Published In

Volume / Issue

  • 21 / 12

Start / End Page

  • 1648 - 1659

PubMed ID

  • 25500222

Pubmed Central ID

  • PMC4272656

Electronic International Standard Serial Number (EISSN)

  • 1879-1301

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2014.10.016


  • eng

Conference Location

  • United States