Unmet Need / Invention Novelty: Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors are known synthetic lethal partners for breast cancer gene (BRCA) 1- and 2-deficient cancers. However, not all BRCA-deficient cancers are susceptible to PARP1 inhibitors and others develop resistance. Furthermore, DNA polymerase beta is overexpressed in many cancers, decreasing the efficacy of anticancer agents that target DNA. There is therefore an unmet need to identify novel synthetic lethal partners with selective inhibitors for treatment of BRCA-deficient cancers. There is also an unmet need to identify molecules that selectively inhibit DNA polymerase beta.
Technical Details: Researchers at Johns Hopkins have demonstrated a novel synthetic lethal for BRCA1 deficient cancers with DNA polymerase beta. They have also discovered covalent inhibitors of DNA polymerase beta for treatment with BRCA-deficient cancer through synthetic lethality. The researchers have demonstrated selectivity of the inhibitors for DNA polymerase beta and have characterized the mechanism of action of the inhibitors.
Value Proposition:
- in vitro validation of polymerase beta as a novel synthetic lethal partner to BRACA1
- Novel compositions selectively and irreversibly inhibit polymerase beta
- Effective induction of synthetic lethality in BRCA deficient cancers
- Low cytotoxicity in BRCA1-proficient cells
- Synergistic cytoxicity with DNA damaging agents
Looking for Partners to: Develop and commercialize as a novel synthetic lethal target and treatment for BRCA deficient cancer.
Stage of Development: Pre-Clinical
Data Availability: in vitro
Inventors: Marc Greenberg & Shelby Yuhas
Patent Status: Provisional patent application filed.
Publication(s): Yuhas et. al. 2021. Selective inhibition of DNA polymerase β by a covalent inhibitor. J. Am. Chem. Soc., 143(21):8099-8107; Yuhas et al. 2021. Suppression of DNA Polymerase b Activity is Synthetically Lethal in BRCA1-Deficient Cells. ACS Chem Biol.
