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

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. doi: 10.1016/j.chembiol.2014.10.016.
Matthew K Howe 1,  Khaldon Bodoor 2,  David A Carlson 1,  Philip F Hughes 1,  Yazan Alwarawrah 1,  David R Loiselle 1,  Alex M Jaeger 1,  David B Darr 3,  Jamie L Jordan 3,  Lucas M Hunter 3,  Eileen T Molzberger 4,  Theodore A Gobillot 5,  Dennis J Thiele 6,  Jeffrey L Brodsky 5,  Neil L Spector 1,  Timothy A J Haystead 7
Affiliations

Affiliations

  • 1 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
  • 2 Department of Applied Biology, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan.
  • 3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 4 Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
  • 5 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • 6 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
  • 7 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: [email protected].
PMID: 25500222 DOI: 10.1016/j.chembiol.2014.10.016
Abstract

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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