Designing a Safer Cancer Drug that Protects the Heart
by Amanda Chase, PhD
November 20, 2025
Blocking cancer-driving proteins is a cornerstone of modern precision medicine, but turning these insights into safe, effective therapies is often challenging. One such protein, BRD9, a chromatin-modifying factor essential for the growth of certain tumors, has been an attractive drug target for years. Early clinical attempts to block BRD9 showed promise in killing cancer cells, but the therapeutic candidates caused dangerous heart rhythm disturbances in patients, bringing drug development to a halt.
A new collaborative study between the Nathanael Gray Lab (Department of Chemical & Systems Biology) and Anna Hnatiuk in Mark Mercola’s lab at the Stanford Cardiovascular Institute has now identified a new class of BRD9-targeting molecules that destroy BRD9 in tumor cells while sparing heart cells, overcoming this major barrier to clinical use. The work was recently published in the Journal of the American Chemical Society.
Researchers have known that disabling BRD9 can impair the growth of aggressive cancers such as synovial sarcoma. Companies developed early BRD9 “degrader” drugs that worked by removing BRD9 from cells rather than just blocking it. In patients, these molecules caused QT prolongation, a serious electrical disturbance of the heart, and offered limited benefit against tumors, leading clinical trials to stop.
In this new study, the researchers designed next-generation versions of BRD9 degraders using a novel covalent “molecular glue” strategy and performed the side-by-side safety testing in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to ensure cardiac protection.
The team added a small cysteine-reactive chemical group to an existing BRD7/9 inhibitor. This change turned the inhibitor into a molecular glue degrader that brings BRD9 closer to a cellular recycling enzyme, DCAF16, leading to rapid destruction of BRD9 within tumor cells. This approach yielded several distinct molecules, leading to a lead compound called ZZ7. Interestingly, ZZ7 was found to eliminate BRD9 in synovial sarcoma cells via a mechanism distinct from those of other degraders in development.
Researchers created a molecular glue degrader (ZZ7; left) that brings BRD9 closer to DCAF16 for rapid destruction within tumor cells (middle). Heart cells have very little DCAF16, so ZZ7 does not degrade BRD9, and therefore does not disrupt heart cell function (right).
As an important consideration, the research team leveraged the iPSC-CM platform to determine if ZZ7 showed any cardiotoxicity, which was observed in earlier BRD9 drugs. Critically, they found that ZZ7 did not disrupt the normal function of the heart cells (iPSC-CMs). The heart cells also showed much lower expression of DCAF16 compared to tumor cells, likely why ZZ7 can selectively degrade BRD9 in cancer cells, and does not risk the heart.
Together, the results from this study show that selective degradation of BRD9 by ZZ7 can be achieved without risking cardiotoxicity, an important advance for the field and for patient health.
The result is a collaboration that resulted in a molecule that appears both more effective against tumors and safer for the heart. The collaborative work between the Gray lab and the Mercola lab demonstrates how combining multi-disciplinary expertise can lead to critical advances.
Stanford researchers include co-first authors Woong Sub Byun and Zhe Zhuang and senior author Nathanael Gray, all members of Sarafan ChEM-H at Stanford, as well as Stanford Cardiovascular Institute members Anna Hnatiuk and Mark Mercola. Evelyn Chao and Zixuan Jiang are also Stanford team members. They are joined by researchers from the Dana-Farber Cancer Institute and Harvard Medical School.
Dr. Anna Hnatiuk
Dr. Nathanael Gray
Dr. Mark Mercola