Abstract：
UNASSIGNED: The multi-subunit SWI/SNF chromatin remodeling complex is a key epigenetic regulator for many cellular processes, and several subunits are found to be mutated in human cancers. The inactivating mutations of SMARCA4, the ATPase subunit of the complex, result in cellular dependency on the paralog SMARCA2 for survival. This observed synthetic lethal relationship posits targeting SMARCA2 in SMARCA4-deficient settings as an attractive therapeutic target in oncology.
UNASSIGNED: This review covers patent literature disclosed during the 2019-30 June 2023 period which claim ATPase inhibitors and PROTAC degraders that bind to the ATPase domain of SMARCA2 and/or SMARCA4. A total of 16 documents from 6 applicants are presented.
UNASSIGNED: The demonstration of cellular dependence on SMARCA2 ATPase activity in SMARCA4-deficient settings has prompted substantial research toward SMARCA2-targeting therapies. Although selectively targeting the ATPase domain of SMARCA2 is viewed as challenging, several ATPase inhibitor scaffolds have been disclosed within the last five years. Most early compounds are weakly selective, but these efforts have culminated in the first dual SMARCA2/SMARCA4 ATPase inhibitor to enter clinical trials. Data from the ongoing clinical trials, as well as continued advancement of SMARCA2-selective ATPase inhibitors, are anticipated to significantly impact the field of therapies, targeting SMARCA4-deficient tumors.
UNASSIGNED: This review covers patent literature disclosed during the 2019-30 June 2023 period which claim ATPase inhibitors and PROTAC degraders that bind to the ATPase domain of SMARCA2 and/or SMARCA4. A total of 16 documents from 6 applicants are presented.
UNASSIGNED: The demonstration of cellular dependence on SMARCA2 ATPase activity in SMARCA4-deficient settings has prompted substantial research toward SMARCA2-targeting therapies. Although selectively targeting the ATPase domain of SMARCA2 is viewed as challenging, several ATPase inhibitor scaffolds have been disclosed within the last five years. Most early compounds are weakly selective, but these efforts have culminated in the first dual SMARCA2/SMARCA4 ATPase inhibitor to enter clinical trials. Data from the ongoing clinical trials, as well as continued advancement of SMARCA2-selective ATPase inhibitors, are anticipated to significantly impact the field of therapies, targeting SMARCA4-deficient tumors.
摘要：
■多亚基SWI/SNF染色质重塑复合物是许多细胞过程的关键表观遗传调节因子，在人类癌症中发现了几个亚基突变。复合体的ATPase亚基SMARCA4的失活突变，导致细胞依赖旁系SMARCA2生存。这种观察到的合成致死关系认为在SMARCA4缺陷设置中靶向SMARCA2是肿瘤学中有吸引力的治疗靶标。
■本综述涵盖了在2019-2023年6月30日期间公开的专利文献，该专利文献要求与SMARCA2和/或SMARCA4的ATPase结构域结合的ATPase抑制剂和PROTAC降解物。共提交了来自6名申请人的16份文件。
■在缺乏SMARCA4的环境中，细胞对SMARCA2ATPase活性的依赖性的证明促使对SMARCA2靶向疗法的大量研究。尽管选择性靶向SMARCA2的ATPase结构域被认为具有挑战性，在过去的五年中，已经公开了几种ATP酶抑制剂支架。大多数早期化合物的选择性较弱，但这些努力最终导致首个双重SMARCA2/SMARCA4ATP酶抑制剂进入临床试验.来自正在进行的临床试验的数据，以及SMARCA2选择性ATP酶抑制剂的持续发展，预计将对治疗领域产生重大影响，靶向SMARCA4缺陷型肿瘤。
■本综述涵盖了在2019-2023年6月30日期间公开的专利文献，该专利文献要求与SMARCA2和/或SMARCA4的ATPase结构域结合的ATPase抑制剂和PROTAC降解物。共提交了来自6名申请人的16份文件。
■在缺乏SMARCA4的环境中，细胞对SMARCA2ATPase活性的依赖性的证明促使对SMARCA2靶向疗法的大量研究。尽管选择性靶向SMARCA2的ATPase结构域被认为具有挑战性，在过去的五年中，已经公开了几种ATP酶抑制剂支架。大多数早期化合物的选择性较弱，但这些努力最终导致首个双重SMARCA2/SMARCA4ATP酶抑制剂进入临床试验.来自正在进行的临床试验的数据，以及SMARCA2选择性ATP酶抑制剂的持续发展，预计将对治疗领域产生重大影响，靶向SMARCA4缺陷型肿瘤。
