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Txinno Bioscience - Model ULK1 -Inhibitor
RAS GTPase family has 3 members encoding KRAS, HRAS and NRAS proteins which are involved in controlling normal growth signal. RAS GTPases are also well-known oncogenes that drive tumorigenesis when mutation is acquired.
RAS pathway and cancer
RAS oncogene mutations have been documented in more than 25% of total cancer patients worldwide and in cancer patients of Lung, Colon and Pancreas with high frequencies, especially. There were many attempts to find the effective drug to treat cancer patients with RAS mutation for last 40 years without success. Consequently, RAS protein was considered as undruggable target. However, impressive clinical responses were observed in trial of Lumakras (sotorasib, Merck) utilizing compound’s ability to form covalent bond with cysteine specifically in KRASG12C mutated cancer (14% of KRAS mutated cancers). The successful approval of Lumakras is driving hope and anticipation of developing therapeutics to treat KRAS mutated cancer.
At Txinno Bioscience, we are developing ULK1 inhibitor (best-in-class), “target S” inhibitor (first-in-class) and "target Y“ inhibitor (first-in-class) to treat cancer patients with KRAS mutations.
ULK1 is a serine/threonine protein kinase that involved in initiating autophagy process when cells encounter stressful conditions, like starvation or oxidative assaults. Autophagy has been known to play important roles in survival, drug resistance as well as immune avoidance of cancer cells. Interestingly, inhibition of ULK1 has been reported to enhance the efficacy of MEK kinase inhibitor when KRAS-mutated cancer cells were subjected to inhibition of both kinases simultaneously (Bryan D. Smith, et. al. (2019) AACR-EORTC poster presentation).
At Txinno Bioscience, we are developing a small molecule ULK1 inhibitor based on concept of synthetic lethality relationship between ULK1 and MEK protein kinases with distinct advantages; 1) in compared to KRASG12C inhibitors, like Lumakras, combination treatment of ULK1 and MEK inhibitors will be effective to patients with KRAS G12C mutation but also to patients with other KRAS mutations, 2) there is a possibility of similar or higher clinical effectiveness with same or reducing dose of MEK inhibitor.