特异性诱导酸性核质 DNA 结合蛋白 1 (And1) 的降解是一种有前景的抗肿瘤策略。我们之前的研究将 Bazedoxifene (BZA) 和 CH3 确定为特定的 And1 降解剂，并验证了它们在体外和体内逆转放疗耐药性的活性。然而，未阐明的结构-活性关系和适度的活性限制了它们的应用。在本研究中，基于And1的WD40结构域的空腔拓扑，设计并合成了27种新颖的CH3衍生物。其中，具有“V”构象的A15在NSCLC细胞中显着诱导And1降解。此外，这项研究证明了 And1 降解剂和 PARP1 抑制剂的潜在合成致死作用。 1μM 奥拉帕尼与 5μM A15 联合显着抑制 A549 和 H460 细胞的增殖。总体而言，这些化合物是阐明 And1 生物学的宝贵工具，其特殊的空间构象使它们成为未来优化研究的有希望的候选者。

Specifically inducing the degradation of acidic nucleoplasmic DNA-binding protein 1 (And1) is a promising antitumor strategy. Our previous study identified Bazedoxifene (BZA) and CH3 as specific And1 degraders and validated their activity in reversing radiotherapy resistance in vitro and in vivo. However, unelucidated structure-activity relationships and moderate activity have limited their application. In this study, 27 novel CH3 derivatives were designed and synthesised based on the cavity topology of the WD40 domain of And1. Among them, A15 with a "V" conformation significantly induced And1 degradation in NSCLC cells. In addition, this study demonstrated a potential synthetic lethal effect of And1 degraders and PARP1 inhibitors. 1 µM of Olaparib in combination with 5 µM of A15 significantly inhibited the proliferation of A549 and H460 cells. Overall, these compounds are valuable tools for elucidating And1 biology, and their special spatial conformation make them promising candidates for future optimisation studies.