Faculty, Staff and Student Publications
Publication Date
5-8-2025
Journal
Journal of Medicinal Chemistry
Abstract
Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, including SMARCA4 in nonsmall cell lung cancer with a frequency of up to 33% in advanced-stage disease, making it the most frequently mutated complex. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating that SMARCA2 is a high-value therapeutic target. Here, we disclose the discovery and characterization of potent, selective, and orally bioavailable cereblon-based SMARCA2 PROTACs. Biochemically, we showed that YDR1 and YD54 are potent SMARCA2 degraders. Further, we showed the antitumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 mutant xenografts. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit the growth of SMARCA4 and KRAS G12C comutant lung cancer cells. These findings provide evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics against SMARCA4 mutant cancers.
Keywords
Animals, Female, Humans, Mice, Administration, Oral, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, DNA Helicases, Drug Discovery, Drug Synergism, Lung Neoplasms, Mice, Nude, Nuclear Proteins, Proteolysis, Proto-Oncogene Proteins p21(ras), Structure-Activity Relationship, Transcription Factors, Xenograft Model Antitumor Assays, Piperazines, Pyridazines
DOI
10.1021/acs.jmedchem.4c02577
PMID
40280558
PMCID
PMC12067438
PubMedCentral® Posted Date
4-25-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons