Synthetic lethality: targeting the SMARCA2 bromodomain for degradation in SMARCA4-deficient tumors – a review of patent literature from 2019–June 2023

Review

作者: Reichl, Kyle D. ; Gopalsamy, Ariamala ; Lee, Esther C. Y.

INTRODUCTIONSMARCA2 and SMARCA4 are subunits of the SWI/SNF complex which is a chromatin remodeling complex and a key epigenetic regulator that facilitates gene expression. Tumors with loss of function mutations in SMARCA4 rely on SMARCA2 for cell survival and this synthetic lethality is a potential therapeutic strategy to treat cancer.AREAS COVEREDThe current review focuses on patent applications that claim proteolysis-targeting chimeras (PROTAC) degraders that bind the bromodomain site of SMARCA2 and are published between January 2019-June 2023. A total of 29 applications from 9 different applicants were evaluated.EXPERT OPINIONSMARCA2/4 bromodomain inhibitors do not lead to desired effects on cancer proliferation; however, companies have converted bromodomain binders into PROTACs to degrade the protein, with a preference for SMARCA2 over SMARCA4. Selective degradation of SMARCA2 is most likely required to be efficacious in the SMARCA4-deficient setting, while allowing for sufficient safety margin in normal tissues. With several patent applications disclosed recently, interest in targeting SMARCA2 should continue, especially with a selective SMARCA2 PROTAC now in the clinic from Prelude Therapeutics. The outcome of the clinical trials will influence the evolution of selective SMARCA2 PROTACs development.

Discovery of Novel, Potent and Orally Bioavailable SMARCA2 PROTACs with Synergistic Anti-tumor Activity in Combination with KRAS G12C Inhibitors

Article

作者: Blazanin, Nicholas ; Liang, Xiaobing ; Wang, Yawen ; Jiang, Yongying ; Kotagiri, Sasikumar ; Nguyen, Phuong Kieu ; Han, Yanyan ; Lissanu, Yonathan

ABSTRACTCancer 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.

YAP1 status defines two intrinsic subtypes of LCNEC with distinct molecular features and therapeutic vulnerabilities

作者: Zhang, Hao Helen ; Fang, Yinshan ; Que, Jianwen ; Ding, Hongxu ; Wang, Ziyuan ; Hao, Ning ; Liu, Ziyang ; Sun, Xiaoxiao

AbstractLarge 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.

100 项与 SMARCA2降解剂(SK Life Science) 相关的药物交易

登录后查看更多信息