Bicyclic compounds as inhibitors of wrn
New compounds are designed to powerfully disrupt WRN helicase, a DNA-repair enzyme cancer cells with microsatellite instability depend upon.
Tumors with high MSI/dMMR signatures are particularly vulnerable to this inhibition, while healthy tissues are largely spared.
These drugs act through a novel mechanism, distinct from immunotherapies, and can potentially overcome therapy resistance.
The compounds may provide much-needed options for patients resistant to checkpoint inhibitors, broadening cancer treatment possibilities.
This patent describes a new class of pharmaceutical compounds designed to block a crucial enzyme, WRN helicase, which plays a key role in maintaining the integrity of human DNA. Dysfunction of WRN is connected not only to premature aging, but also to the survival of certain aggressive tumors—specifically those with high levels of microsatellite instability (MSI-H) or deficient mismatch repair (dMMR).
Advances in cancer genomics revealed that many MSI-H/dMMR cancers, including a significant percentage of endometrial, colon, and stomach tumors, are especially reliant on WRN activity for their survival. When WRN is shut off in these cancer cells, their DNA can’t be properly managed or repaired, leading to cell death. However, tumors that lack this genomic signature (microsatellite stability) are left largely unharmed, indicating the target’s selectivity.
Existing treatments for these cancer types, such as immune checkpoint inhibitors (CPIs) like pembrolizumab and newer drug combinations, have brought progress but also face limitations: not all patients respond well, and resistance is common. WRN-targeting compounds introduce a fundamentally different biological approach, directly undermining cancer cell survival by preventing the WRN enzyme from carrying out its ATP-powered unwinding action necessary for DNA repair and replication.
The patent outlines several forms of the new inhibitors, methods of placing them into suitable pharmaceutical preparations, and strategies for clinical use. These compounds either block WRN’s ability to unwind DNA (helicase activity), stop its energy source (ATPase activity), or both. Preclinical models suggest that these agents remain effective even in cancers that have already become resistant to standard therapies, including targeted agents, chemotherapy, or immunotherapy.
This innovation may transform treatment for patients with MSI-H/dMMR tumors, especially those who have exhausted other options. WRN inhibitors could be used alone or in combination with current approaches, offering hope of overcoming resistance, increasing the breadth of treatable cancers, and minimizing collateral damage to normal, non-cancerous cells.