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.