Tricyclic compounds as inhibitors of wrn
Compounds selectively target WRN helicase, crippling DNA repair in MSI-H/dMMR cancers while sparing healthy cells.
These drugs work via a mechanism independent of immunotherapy, providing new options for resistant tumors.
Preclinical research shows effectiveness even where standard chemotherapy, targeted drugs, and immunotherapy no longer work.
By filling a major treatment gap, WRN inhibitors could reshape therapeutic possibilities for a significant subset of hard-to-treat cancers.
This patent introduces a novel class of pharmaceutical compounds crafted to interfere with the enzyme Werner helicase (WRN), a key player in maintaining DNA integrity and cellular stability. The WRN enzyme, a member of the RecQ helicase family, is indispensable for cellular DNA repair and chromosome stability. However, certain aggressive cancers—specifically those with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR)—become dangerously reliant on WRN’s function for survival.
Scientific screening has revealed a pronounced dependence on WRN for the survival of MSI-H cancer cells. When WRN is removed or inhibited, these vulnerable cancer cells lose their ability to efficiently repair DNA, leading to halted growth and cell death. In contrast, cancers that do not exhibit microsatellite instability remain largely unaffected by the absence of WRN, pointing to a highly selective vulnerability that these new compounds exploit.
Traditional treatment options for MSI-H/dMMR cancers, such as immune checkpoint inhibitors, have shown benefit but come with challenges: response rates remain modest, and some patients develop resistance. The compounds described in this patent employ a fundamentally different approach, undermining cancer cell survival by obstructing WRN’s adenine triphosphate (ATP)-driven mechanisms—specifically its ability to unwind DNA and to hydrolyze ATP, both essential for DNA repair and cancer growth.
A particularly compelling aspect of these WRN inhibitors is their potential application in overcoming treatment resistance. Preclinical evidence suggests that even cancers with established resistance to chemotherapy, targeted treatments, or immunotherapy remain susceptible to WRN inhibition. This opens new avenues for patients whose tumors have failed to respond to existing therapies.
The patent outlines the structural makeup of these inhibitors, their pharmaceutical formulations, and potential treatment regimens. The envisioned uses extend beyond monotherapy: these compounds are intended to be versatile, with the potential to combine with other modern therapies—such as checkpoint inhibitors—for a more comprehensive attack on difficult-to-treat cancers. This innovation positions WRN inhibitors as a promising class of targeted treatment—precise, selective, and potentially transformative for patients with MSI-H/dMMR malignancies.