SMARCA2 degrader(SK Life Science)

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex includingSMARCA4in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. We and others have identifiedSMARCA2to be synthetic lethal toSMARCA4,indicating 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, YDR1 and YD54 are potent SMARCA2 degraders with an average DC50of 7.7nM and 3.5nM respectively inSMARCA4mutant lung cancer cells. Phenotypically, both YDR1 and YD54 selectively inhibited growth ofSMARCA4mutant cancer cells. Further, we showed anti-tumor growth inhibitory activity of YDR1 and YD54 inSMARCA4mutant xenograft models of lung cancer. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit growth ofSMARCA4andKRAS G12Cco-mutant lung cancer cells. These findings provide additional evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics againstSMARCA4mutant cancers.

Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like the more common small cell lung cancer (SCLC), is associated with an absence of druggable oncogenic driver mutations, a clinically aggressive disease course, and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies which are, instead, often adapted from SCLC and non-small cell lung cancer (NSCLC) approaches. While there have been some efforts to describe the molecular landscape of LCNEC, to date there are few links between distinct biologic phenotypes of LCNEC and therapeutic vulnerabilities. Here, we demonstrate that the presence or absence of the transcription factor YAP1 distinguishes two roughly equal subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and characterized, alongsideTP53mutations, by co-occurring alterations inCDKN2A/BandSMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK and AXL targeting strategies, including a novel preclinical AXL CAR-T cell, as well as predicted vulnerability to SMARCA2 degraders and CDK4/6 inhibitors. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly featuresTP53andRB1co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by expression of SCLC subtype-defining transcription factors -especially ASCL1 and NEUROD1 - and, as expected given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including Delta-like ligand 3 (DLL3) and CD56 targeting, as with novel preclinical DLL3 and CD56 CAR T-cells, and DNA damage repair (DDR) inhibition. These findings highlight the potential for YAP1 to guide the first personalized treatment strategies for LCNEC.