Yonathan Lissanu Deribe, PhD, MD

Despite recent advances, the majority of patients with lung cancer lack effective therapeutic options. There is a dire need for additional treatment approaches. DNA sequencing studies have identified frequent mutations in a gene known as SMARCA4 in 15% of advanced lung cancers. We have recently identified a gene named SMARCA2 that is required for growth of SMARCA4 mutant lung cancer. However, identifying selective inhibitors of SMARCA2 has been challenging. We have now developed novel SMARCA2 degrading small molecules based on a new drug-development technology called proteolysis targeting chimera (PROTAC). We demonstrated that a compound called YD23 potently and selectively induces degradation of SMARCA2. We further showed that YD23 selectively inhibits growth of SMARCA4 mutant lung cancer cells. Our findings will be used to guide future development of YD23 in patients with SMARCA4 mutant lung cancer.

Update:
Lung cancers harboring the SMARCA4 mutation have a poor prognosis and lack effective treatment options, underscoring the urgent need to discover and develop novel therapeutic approaches. To address this, we have developed novel SMARCA2-degrading small molecules based on the proteolysis targeting chimera (PROTAC) technology. We have identified a tolerable dose of SMARCA2 PROTAC for efficacy studies in mice. Further, we showed that SMARCA2 PROTACs actively induced degradation of SMARCA2 in mice, highlighting their potential for future clinical translation. During the second year of the award, we intend to perform anti-tumor efficacy studies in mice to determine the utility of these compounds as potential therapeutics.

Final Project Update: 
Lung cancer is the leading cause of cancer-related deaths. Despite recent advances, many patients still lack effective treatment options, highlighting the urgent need for new therapies. Genomic studies of non-small cell lung cancer have found frequent mutations in a large, multiprotein complex called the SWI/SNF chromatin remodeling complex, particularly in subunits like SMARCA4. Mutations occur in up to 33% of advanced cases. This makes it the most commonly mutated protein complex in lung cancer. 

Recent research indicates that SMARCA2, a related protein, is crucial for cells with SMARCA4 mutations, suggesting it could be a promising target for therapy. However, developing specific inhibitors for SMARCA2 has been difficult. To address this, we conducted studies to create new small molecules that selectively degrade SMARCA2 using cutting-edge technology called proteolysis targeting chimera (PROTAC). 

We identified a drug called YD23 that effectively and selectively degrades SMARCA2. YD23 also strongly inhibits tumor growth in SMARCA4 mutant models in mice. These results support the development of SMARCA2 degraders as targeted therapies for tumors with SMARCA4 mutations.