# The Development of Organelle Specific Hsp90 Isoform-Selective Inhibitors

> **NIH NIH K00** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $85,399

## Abstract

Project Summary
The 90 kDa heat shock proteins (Hsp90) are chaperones responsible for the maturation of approximately 200
protein substrates (clients). Many of these client proteins are involved in cellular signaling pathways essential to
regulating cell survival and proliferation. Inhibition of Hsp90 represents an attractive approach for the
development of anticancer therapeutics due to the large number of important proteins dependent upon Hsp90
providing the unique opportunity to simultaneously inhibit multiple oncogenic signaling pathways. There are four
Hsp90 isoforms, all with different a subset of client proteins. Selective inhibition of each isoform is desirable to
reduce the number of client proteins affected and reducing the risk of toxicities. The development of organelle
specific Hsp90 isoform-selective inhibitors is proposed in order to elucidate which client proteins are dependent
upon these isoforms and determine which types of cancer rely heavily upon each subset. The endoplasmic
reticulum localized isoform (Grp94) is responsible for the maturation of proteins associated with cell motility which
has applications toward decreasing cancer metastasis. Metastasis is one of the leading causes of cancer related
deaths because each new metastatic lesion leads to a worse prognosis. Inhibition of Grp94 provides the
opportunity to selectively inhibit cancer metastasis without producing any toxicities due to Grp94 being non-
essential to cell survival. Thus, Grp94-selective inhibition providing a novel approach to decreasing metastasis
and improving patient prognosis. Similarly, the development of isoform-selective inhibitors of the mitochondria
localized Hsp90 isoform (Trap1) will be pursued. One client of Trap1 (B-Raf) is often mutated to a constitutively
active form providing the driving force behind aggressive melanomas. Inhibitors of B-Raf have been approved
by the FDA, however, resistance often occurs through mutations rendering these B-Raf inhibitors ineffective.
Trap1-selective inhibition will decrease levels of both B-Raf and mutant B-Raf reducing the occurrence of
resistance in this aggressive form of cancer. Organelle specific Hsp90 isoform-selective inhibitor provide novel
and unique therapeutic options to inhibit the progression of progression of aggressive cancers.

## Key facts

- **NIH application ID:** 10078856
- **Project number:** 5K00CA212467-06
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Vincent Crowley
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $85,399
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078856

## Citation

> US National Institutes of Health, RePORTER application 10078856, The Development of Organelle Specific Hsp90 Isoform-Selective Inhibitors (5K00CA212467-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10078856. Licensed CC0.

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