Abstract：
UNASSIGNED: SMARCA2 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.
UNASSIGNED: The 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.
UNASSIGNED: SMARCA2/4 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.
UNASSIGNED: The 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.
UNASSIGNED: SMARCA2/4 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.
摘要：
■SMARCA2和SMARCA4是SWI/SNF复合物的亚基，SWI/SNF复合物是染色质重塑复合物，是促进基因表达的关键表观遗传调节因子。SMARCA4功能缺失突变的肿瘤依赖于SMARCA2细胞存活，这种合成致死性是治疗癌症的潜在治疗策略。
■当前的评论集中在声称与SMARCA2的溴结构域位点结合的蛋白水解靶向嵌合体（PROTAC）降解物的专利申请中，并在2019年1月至2023年6月之间发布。共评估了9个不同申请人的29个申请。
■SMARCA2/4溴结构域抑制剂不会对癌症增殖产生预期效果；然而，公司已经将溴结构域结合剂转化为PROTACs来降解蛋白质，与SMARCA4相比，更喜欢SMARCA2。在缺乏SMARCA4的情况下，SMARCA2的选择性降解很可能是有效的，同时允许正常组织有足够的安全裕度。随着最近披露的几项专利申请，瞄准SMARCA2的兴趣应该继续，特别是现在在临床上使用PreludeTherapeutics的选择性SMARCA2PROTAC。临床试验的结果将影响选择性SMARCA2PROTACs开发的演变。
■当前的评论集中在声称与SMARCA2的溴结构域位点结合的蛋白水解靶向嵌合体（PROTAC）降解物的专利申请中，并在2019年1月至2023年6月之间发布。共评估了9个不同申请人的29个申请。
■SMARCA2/4溴结构域抑制剂不会对癌症增殖产生预期效果；然而，公司已经将溴结构域结合剂转化为PROTACs来降解蛋白质，与SMARCA4相比，更喜欢SMARCA2。在缺乏SMARCA4的情况下，SMARCA2的选择性降解很可能是有效的，同时允许正常组织有足够的安全裕度。随着最近披露的几项专利申请，瞄准SMARCA2的兴趣应该继续，特别是现在在临床上使用PreludeTherapeutics的选择性SMARCA2PROTAC。临床试验的结果将影响选择性SMARCA2PROTACs开发的演变。
