Breakpoint’s pipeline is the result of deep DDR expertise and biology insights combined with a platform of advanced biochemical and cellular assays. To these internal capabilities, we add our access to a broad, international network of academic and industry leaders whose advice contributes to our steady progress.
Breakpoint’s lead programs target DNA Polymerase theta (PolQ) and Werner Syndrome Helicase (WRN). These two well-validated oncology targets hold great therapeutic potential for the unmet medical needs of distinct patient groups. Beyond these programs, we continue to translate early-stage discovery research into novel opportunities to build out our pipeline of DDR drug candidates.
Target ID & Validation
Assay Dev & Screening
Lead Generation & Lead to Candidate
POL THETA INHIBITORS targeting microhomology mediated end-joining reliant tumours.
Pharmacologic leads against both functional domains of this key mediator of MMEJ.
WRN INHIBITORS potentiating replication stress in MSI-high tumours.
Compounds inhibiting helicase essential in MSI-high cells.
DNA Polymerase Theta
DNA polymerase theta (PolQ) is a low fidelity DNA repair enzyme with multiple functions, including polymerase and helicase activity. It is overexpressed in many cancers, but is not essential in normal cells.
Functionally, PolQ is a critical component of microhomology mediated end joining (MMEJ), a pathway used by cells to process DNA double strand breaks when primary repair pathways are defective. The most prominent DDR deficiency in tumors that results in MMEJ dependency is the loss of homologous recombination (HR) repair. PolQ enables such DNA repair-deficient tumor cells to survive DNA damage but its activity creates additional mutations and genetic alterations which can facilitate tumor evolution and drug resistance. Moreover, high levels of PolQ correlate with poor prognosis and therapy resistance. Inhibiting PolQ therefore offers a new therapeutic option for a broad range of patients, either alone or when combined with other treatments.
Werner Syndrome Helicase (WRN)
Werner Syndrome helicase (WRN) is integral to the processing of complex DNA secondary structures; these especially occur in cancer cells under conditions of DNA replication stress. Utilizing helicase and nuclease functions, WRN resolves DNA secondary structures and facilitates recovery of stalled replication forks.
Cells with a deficiency in the DNA mismatch repair (MMR) pathway accumulate mutations over time and often progress towards becoming cancerous. Such cells frequently display a characteristic called microsatellite instability (MSI). In contrast to normal cells, MSI-high cancer cells are strictly dependent on WRN helicase function to survive. Most MSI-high cancers develop resistance to currently available therapies, and thus patients are urgently in need of innovative and effective treatment options. Breakpoint’s development of a WRN-specific therapy may hold the key to more effective outcomes in a range of hard-to-treat cancers.