How a chemical ‘backdoor’ re-sensitizes drug-resistant ovarian cancer by pulling the plug on DNA repair
One of the most frustrating patterns in oncology is the tumor that initially responds to a drug and then stops: the inevitable emergence of resistance. For PARP inhibitors — a class of drug that has transformed treatment of BRCA-mutant ovarian and breast cancers by exploiting the tumor’s weakness in DNA repair — resistance has been a particularly stubborn problem. Tumors find ways to restore their DNA repair capacity, and the drug stops working.
A paper published April 4 in Nature Communications by researchers at South Korea’s Institute for Basic Science (IBS) and Chungnam National University describes a new approach to reversing that resistance — one that works not by attacking the DNA repair machinery directly, but by pulling the cellular plug that powers it.
The compound, called UNI418, is a small molecule that triggers the degradation of three key homologous recombination (HR) proteins — RAD51, CHK1, and CtIP — through a mechanism that surprised even the researchers who discovered it.
The finding is notable in part because of what UNI418 is not. The most widely discussed approach to targeted protein degradation in recent years has been PROTACs (proteolysis-targeting chimeras) — bifunctional molecules that kidnap a target protein and physically drag it to the cell’s garbage disposal. UNI418 does something fundamentally different.
The compound is a derivative of ML367, originally identified as an inhibitor of ATAD5 stabilization. Through a high-throughput screen for molecules that modulate the DNA replication stress response, the team — led by co-first authors Seon-gyeong Lee, Yuri Seo, and Seula Jeong, and co-corresponding authors Kyungjae Myung (Director of the IBS Center for Genomic Integrity) and Joo-Yong Lee (Chungnam National University) — found that UNI418 works by inhibiting two lipid kinases, PIKfyve and PIP5K1C.
This inhibition reduces intracellular levels of inositol hexaphosphate (IP6), a signaling molecule that normally suppresses a ubiquitin ligase complex called Cul4A-WDR5. When IP6 levels drop, Cul4A-WDR5 is unleashed, tagging RAD51, CHK1, and CtIP for proteasomal destruction.
“It’s a backdoor approach,” said Myung in the IBS press release. “We are not designing a molecule to directly grab RAD51, as with PROTACs. Instead, we are hijacking the cell’s own protein degradation machinery by removing a natural brake on ubiquitination.”
The data
In cell lines derived from olaparib-resistant ovarian cancers, UNI418 sharply reduced levels of RAD51, CHK1, and CtIP within hours. The subsequent loss of homologous recombination capacity re-sensitized the cells to PARP inhibitor treatment. In xenograft mouse models, the combination of UNI418 and olaparib suppressed tumor growth significantly better than either agent alone, including in models specifically designed to mimic treatment-resistant disease.
The specificity is worth noting: UNI418 degrades three proteins, not one, which makes the development of secondary resistance more difficult — a tumor would need to find a way around a multi-protein vulnerability rather than mutating a single target.
The context
PARP inhibitors like olaparib, niraparib, and rucaparib have been a mainstay of BRCA-mutant cancer treatment for over a decade. They work by exploiting synthetic lethality: BRCA-mutant tumors are already deficient in homologous recombination, and PARP inhibition pushes them over the edge by blocking a second repair pathway. But resistance emerges through multiple mechanisms — restoration of HR function, drug efflux, and compensatory signaling pathways — and effective salvage strategies remain limited.
UNI418’s approach — indirectly degrading HR proteins from beneath — is agnostic to the resistance mechanism. Whether the tumor restored HR through BRCA reversion, RAD51 overexpression, or checkpoint adaptation, UNI418 collapses the repair system from the bottom.
The compound is not yet in clinical trials. The authors describe it as a tool compound and a starting point for medicinal chemistry optimization. The 33-author team includes scientists from IBS’s Center for Genomic Integrity in Ulsan, Chungnam National University, and collaborating institutions across South Korea.
Source: Lee, S.-G., Seo, Y., Jeong, S. et al. “Targeting IP6 signaling to destabilize homologous recombination proteins to overcome PARP inhibitor resistance.” Nature Communications (2026). DOI: 10.1038/s41467-026-71421-z. Published 4 April 2026. Open access.