Autophagy (“self-eating”) refers to a fundamental cellular process for eliminating damaged components. In this process, cells respond to various stresses by destroying their own contents through the transport of vesicles to a recycling compartment (called the lysosome) for degradation. ULK1 is a protein kinase that initiates autophagy upon activation by upstream nutrient deprivation signals.
ULK1 recently has emerged as a promising target for cancer. Recent studies indicate that tumor cell metabolism depends on a highly active autophagy pathway. Genetic disruption of ULK1 has been shown to inhibit development of multiple cancers, including glioblastoma and pancreatic cancer, both of which are currently incurable diseases. MSK investigators have identified several initial hits through a high throughput screen, and conducted a medicinal chemistry campaign to optimize these hits. The current lead compounds are potent inhibitors of ULK1.
Autophagy inhibitors could have broad utility in treating several different tumor types
- Tumors with RAS/RAF mutations display high levels of autophagy
- MAPK pathway inhibitors can induce autophagy and promote cancer cell survival
- Investigators have developed proprietary in vitro and in vivo models in which to assess the anti-cancer effects of ULK1 inhibitors
Compounds that inhibit the ULK1 complex could demonstrate broad clinical utility in a variety of cancers with unmet needs and high mortality rates, including pancreatic cancer and glioblastoma. In the U.S. an estimated 57,000 patients will be diagnosed with pancreatic cancer and about 46,000 will die of the disease each year. Another 12,000 Americans are diagnosed annually with glioblastoma, the most deadly form of brain cancer.
PCT application PCT/US2020/067323 was filed on Dec. 29, 2020 and is currently pending.
Xeujun Jiang, PhD, Laboratory Head, Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering
James Delorme, PhD, Licensing Manager