Allosteric Modulation of PARP1-DNA Binding with Small Molecule Inhibitors: A Potential None Synthetic Lethal Therapeutic Strategy for Treating Ewing Sarcoma and Other Solid Tumors for Treating Ewing Sarcoma and Other Solid Tumors

Case ID:
2756
Web Published:
7/29/2019
Description:

Summary

Researchers at OHSU have developed a novel PARP1 inhibitors that demonstrate a novel dual mode of action to inhibit catalytic activity while also allosterically trapping PARP1 at the DNA binding stage. This strategy offers a significant advantage over existing PARP1 inhibitors by increasing replication stress and cytotoxicity, potentially eliminating the need for synthetic lethal strategy in the treatment of Ewing Sarcoma and other solid tumors.

Technology Overview

PARP1 inhibitors are effective cancer treatments, but their precise mechanisms of action remain elusive, highlighted by the poor correlation between inhibition of PARP1 catalytic activity and anticancer capabilities. Novel inhibitors developed at OHSU are designed to potently bind and inhibit the PARP1 catalytic domain, effective for some molecules in the subnamolar range, while at the same time allosterically modulating PARP1 to increase DNA binding affinity. Higher DNA binding affinity was associated with increased DNA damage and replication stress as indicated by increased phosphorylation of H2a.x. Compared to traditional PARP1 inhibitors, this novel class of inhibitors showed increased efficacy at inhibiting in vitro cell growth and inducing cell cycle arrest. One particular novel inhibitor was at least 60-fold more cytotoxic for Ewing Sarcoma cells than all FDA-approved PARP1 inhibitors. The novel ability of a single molecule to inhibit PARP1 and also increase replication stress may offer a considerable advantage over existing PARP1 inhibitors by eliminating the need for synthetic lethal therapeutic strategies.  As such, this class of molecules has the potential to be the first PARP1 monotherapy for Ewing Sarcoma and other solid tumors.

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Patent Information:
Category(s):
Therapeutics
For Information, Contact:
Travis Cook
Senior Technology Development Manager
Oregon Health & Science University
cooktr@ohsu.edu
Inventors:
Moriah Arnold
Michael Cohen
Anang Shelat
Keywords:
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