SUMMARY OF INVENTION
A variety of breast and colon carcinomas, as well as the vast majority of acute lymphoblastic and myeloid leukemias (including genetically defined high-risk and refractory leukemias), depend on the aberrant activity of the hematopoietic transcription factor MYB and its co-activators CREB-binding protein (CBP) and its paralogue P300. Cancer cell survival is dependent on the physical formation of this complex.
Despite prior attempts to interfere with this complex, no therapeutic inhibitors blocking the interaction between MYB and its transcriptional co-activators have been successfully developed. MSK scientists have designed a portfolio of novel cell-penetrant peptidomimetic MYB:CBP inhibitors and validated their mechanism-of-action and anti-cancer activity in cancer models in vitro and in vivo. Second- and third-generation inhibitors have recently been designed to improve activity and pharmacologic properties for human use.
- Platform technology includes portfolio of peptidomimetic MYB:CBP inhibitors
- Novel pharmacologic strategy for dismantling MYB:CBP/P300 c0mplexes
- Addresses the historical challenge of interfering with MYB transcription factor activity
- Potential applications include drugging oncogenic transcription factors and other classically undruggable protein-protein interactions
There is a strong unmet need, given that survival rates for AML remain less than 70% and 40% for children and adults, respectively, while distinct subtypes of leukemia are essentially lethal, with no currently effective therapies. AML is the second-most common type of leukemia diagnosed, comprising up to 32% of all adult leukemia cases. In 2018, there were an estimated 19,520 new cases of acute myeloid leukemia in the U.S. Similarly, distinct subsets of breast and colon carcinomas, and brain gliomas depend on the MYB:CBP complex, with many thousands of patients dying from refractory disease every year.
Ramaswamy et al. (2018) Peptidomimetic blockade of MYB in acute myeloid leukemia. Nature Communications (PubMed link)
STAGE OF DEVELOPMENT
PCT application PCT/US2017/059579 filed on November 3, 2017 and published November 5, 2018
Alex Kentsis, MD, PhD, Pediatric Oncologist, Laboratory Head, Molecular Pharmacology Program, Sloan Kettering Institute, MSK