Novel pyrroloquinazolines as anti-cancer agents

Case ID:
1851
Web Published:
10/16/2013
Description:

Summary

Researchers at Oregon Health & Science University have discovered a class of compounds that are biologically active through a novel mechanism of action by inhibiting homologous recombination repair of DNA double-strand breaks. The lead compound is not cytotoxic in normal cells, has proven activity in vivo, and represents a tremendous opportunity to develop the first selective drug for treatment for a variety of cancer types.

Technology Overview

DNA double-strand damages can be repaired by either homologous recombination (HR) or non-homologous end joining (NHEJ). Lamin A promotes genetic stability by maintaining the levels of proteins that have key roles in HR and NHEJ.  Lamin A is an intermediate filament protein that is involved in stabilizing Rad51 protein stability. Compounds in this class bind lamin A to induce Rad51 protein degradation and thus inhibit HR.

Compounds in this class have been shown to inhibit the growth of multiple triple negative breast and ovarian cancer cell lines. In vitro GI50’s for select compounds are low double digit nanomolar.  Note, data for best-in-class compounds are not shown in the data table. Compounds in this class also inhibit the growth of triple negative breast cancer in a xenograph study that utilized MDA-MB-468 cells.

Publications

Xiao, X. et al. “A Lamin-binding Ligand Inhibits Homologous Recombination Repair of DNA Double-Strand Breaks.” ACS Cent Sci 4(2018): 1201-1210. Link

Xiao, X. et al. “Anticancer Pyrroloquinazoline LBL1 Targets Nuclear Lamins.” ACS Chem Biol 13 (2018): 1380-1387. Link

Xiao, X. et al. “Design, synthesis and evaluation of antitumor acylated monoaminopyrroloquinazolines.”, Bioorg Med Chem Lett, 27 (2017): 3107-3110. Link

Xiao, X. et al. “Discovery of a potent anti-tumor agent through regioselective mono-N-acylation of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine.” Med Chem Comm 9 (2013): 1275-1282. Link

Licensing Opportunity

This technology is available for exclusive licensing and/or co-development.

Patent Information:
Category(s):
Therapeutics
Chemical
For Information, Contact:
Lisa Lukaesko
Technology Development Manager
Oregon Health & Science University
lukaesko@ohsu.edu
Inventors:
Xiangshu Xiao
Jingjin Chen
Bingbing Li
Keywords:
Therapeutics - Cancer
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