On September 16, 2021 Endeavor BioMedicines, a clinical-stage precision medicine company targeting the core drivers of multiple terminal diseases including oncology and fibrosis, reported the in-licensing of a ULK1/2 inhibitor program from the Salk Institute for Biological Studies and Sanford Burnham Prebys (Press release, Endeavor BioMedicines, SEP 16, 2021, View Source [SID1234606754]). The license agreement provides Endeavor with exclusive worldwide rights to ENV-201, an orally available small molecule inhibitor of ULK1/2, a critical enzyme in a cellular recycling process called autophagy that is often linked to drug resistance in RAS- and LKB1-mutated cancers. Endeavor plans to complete IND-enabling studies and advance the program into the clinic initially in colorectal and lung cancers in the next 18 months.
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"The Salk Institute and Sanford Burnham Prebys have pioneered early research on the ULK1/2 pathway in RAS-mutated cancers, including those that have become resistant to current standard of care," said John Hood, Ph.D., Co-Founder, CEO and Chairman of Endeavor. "This powerful ULK1/2 program that we have acquired is synergistic with our growing portfolio of precision medicine treatments and has the potential to be an important new treatment option for patients with life-threatening colorectal and lung cancers."
Mutations in the tumor suppressor LKB1 are found in approximately 15% of all people with non-small cell lung cancer and a significant number of individuals with other cancers, including colorectal carcinoma. LKB1 mutations remove a "brake" preventing oncogenesis and are frequently co-mutated with KRAS oncogenes which stimulates oncogenesis. These patients are generally resistant to the standard of care (chemotherapy or immuno-oncology treatment) and face a very poor prognosis. In preclinical models, the ULK1/2 inhibitor ENV-201 demonstrated single-agent activity against these tumors providing a potential therapeutic option where there is none today. Endeavor intends to advance the orally available, small molecule compound as a single-agent treatment, and the company also plans to explore combination treatment with cancer immunotherapy in refractory patients.
"Since we initially discovered how cancer cells starved of nutrients activate ULK1/2, we focused on finding a drug that could block its activity," said Nicholas Cosford, Ph.D., professor and deputy director of the NCI-designated Cancer Center at Sanford Burnham Prebys. "Using medicinal chemistry, chemical biology and rational drug design, we created compounds that inhibit ULK1/2 and we are hopeful this approach will have an impact as an anti-cancer treatment. This agreement with Endeavor BioMedicines moves our efforts closer to our goal of helping people living with cancer."
"We are excited that Endeavor BioMedicines will be advancing the ULK1/2 program into clinical development – a program that has the potential to be an extraordinary therapeutic option for patients who have certain genetically defined, life-threatening cancers," said Reuben Shaw, Ph.D., professor, Molecular and Cell Biology Laboratory, William R. Brody Chair, Salk Institute for Biological Studies. "It is the right time to pass the baton to Endeavor for late preclinical and clinical development, and it underscores the strength of San Diego’s biotech ecosystem for the benefit of patients who have significant unmet medical need."
Targeting a Cellular Recycling Progress in Cancer Biology
The laboratories of Shaw and Cosford collaborated to develop a portfolio of small molecule inhibitors of ULK1/2, a critical enzyme in a cellular recycling process called autophagy. Tumor cells use this cellular recycling process to supply much-needed nutrients and metabolites when there are not enough nutrients in the available blood supply. Tumors with high levels of autophagy are resistant to standard therapies and those patients generally have a very poor prognosis. Researchers have also found that specific genetic mutations frequently found in lung, colorectal and pancreatic cancer make those tumors highly dependent on this recycling pathway. The combined research suggests that drugs targeting ULK1/2 to inhibit autophagy should work well in genetically defined cancers alone or in combination with existing chemo-, targeted- and immuno-therapeutics.