INVENTION NOVELTY
Johns Hopkins researchers have developed multiple unique inhibitors to DNA polymerase beta, a potential anti-cancer therapeutic target.
VALUE PROPOSITION
The DNA damaging agent temozolomide (TMZ) is used to treat melanoma and glioblastoma. TMZ damages cancer cell DNA by introducing single stranded breaks (SSBs). However TMZ’s efficacy is limited, as SSBs can be repaired, preventing efficient cancer cell killing.
DNA polymerase beta helps repair SSBs. Inhibiting it while treating with TMZ is therefore proposed to lead to more unrepaired DNA damage and more efficient cancer cell killing. The inventors have discovered multiple DNA polymerase inhibitors, with a demonstrated anti-cancer effects in vitro when used in conjunction with a DNA damaging agent. Clinicial trials have begun on a separate, emerging class of SSB repair inhibitors, PARP inhibitors, to be used in combination with TMZ to treat various cancers. This activity confirms an unmet need for SSB repair inhibitors in the cancer treatment market.
TECHNICAL DETAILS
The inventors have discovered at least three molecules that bind to and inhibit polymerase beta. These molecules irreversibly inhibit DNA polymerase beta’s SSB repair activity, specifically knocking out its lyase function. The disclosed molecules have IC50’s (molecule concentration required to inhibit total DNA polymerase beta activity by 50%) of 21 uM, 1 uM, and .5uM.
Note, this molecule is intended to be used in conjunction with a DNA alkylating (damaging) agent such as TMZ or methyl methanesulfonate (MMS).
STAGE OF DEVELOPMENT
1st generation inhibitor has demonstrated anti-cancer effects in vitro. 2nd generation inhibitor acts synergistically with MMS in HeLA cells, and exhibits little cytotoxicity on its own. Fewer than 1% of cells survive under conditions where MMS alone kills less than 15% HeLa cells.
Publication/Related Technology:
-Irreversible Inhibition of DNA Polymerase β by Small-Molecule mimics of a DNA Lesion. Arian et al, JACS, 2014.
-JHU Ref. C12546 - US 9029346 - Irreversible inhibitors of DNA polymerase beta
