Arvinas, LLC, 5 Science Park, New Haven, CT, 06511, USA.
Genentech, 1 DNA Way, South San Francisco, 94080, USA.
Nat Commun. 2022 Nov 10;13(1):6814. doi: 10.1038/s41467-022-34562-5.
The mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated in cancer and inactivation results in a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving a high degree of selective SMARCA2 inhibition is likely essential to afford an acceptable therapeutic index, and realizing this objective is challenging due to the homology with the SMARCA4 paralog. Herein we report the discovery of a potent and selective SMARCA2 proteolysis-targeting chimera molecule (PROTAC), A947. Selective SMARCA2 degradation is achieved in the absence of selective SMARCA2/4 PROTAC binding and translates to potent in vitro growth inhibition and in vivo efficacy in SMARCA4 mutant models, compared to wild type models. Global ubiquitin mapping and proteome profiling reveal no unexpected off-target degradation related to A947 treatment. Our study thus highlights the ability to transform a non-selective SMARCA2/4-binding ligand into a selective and efficacious in vivo SMARCA2-targeting PROTAC, and thereby provides a potential new therapeutic opportunity for patients whose tumors contain SMARCA4 mutations.
哺乳动物 SWItch/Sucrose Non-Fermentable (SWI/SNF) 解旋酶 SMARCA4 在癌症中经常发生突变，失活会导致细胞依赖其同源物 SMARCA2，因此使 SMARCA2 成为有吸引力的合成致死靶标。然而，已发表的数据表明，实现高度选择性的 SMARCA2 抑制可能对于提供可接受的治疗指数至关重要，由于与 SMARCA4 同源物的同源性，实现这一目标具有挑战性。本文报道了一种有效的、选择性的 SMARCA2 蛋白水解靶向嵌合体（PROTAC）A947 的发现。在不存在选择性 SMARCA2/4 PROTAC 结合的情况下，实现了选择性 SMARCA2 降解，与野生型模型相比，在 SMARCA4 突变模型中，A947 具有强大的体外生长抑制和体内疗效。全局泛素图谱和蛋白质组分析显示，A947 治疗没有与非预期的脱靶降解相关。因此，我们的研究突出了将非选择性的 SMARCA2/4 结合配体转化为选择性和有效的体内 SMARCA2 靶向 PROTAC 的能力，从而为那些肿瘤含有 SMARCA4 突变的患者提供了新的潜在治疗机会。
