Apoptosis resistance worsens treatment response in cancer and is associated with poor prognosis. Inhibition of anti‐apoptotic proteins can restore cell death and improve treatment efficacy. cIAP1, cIAP2, and XIAP belong to the inhibitor of apoptosis protein (IAP) family and block apoptosis. Targeting IAPs with peptides or peptidomimetics mimicking the IAP‐antagonizing activity of the cell's endogenous IAP antagonist SMAC (SMAC mimetics) showed promising results and fueled development of novel compounds. ASTX660 belongs to the recently introduced class of non‐peptidomimetic IAP antagonists and successfully completed phase I clinical trials. However, ASTX660 has thus far only been evaluated in few cancer entities. Here, we demonstrate that ASTX660 has cell death‐promoting activity in colorectal cancer and provide a head‐to‐head comparison with birinapant, the clinically most advanced peptidomimetic IAP antagonist. ASTX660 facilitates activation of the extrinsic apoptosis pathway upon stimulation with the death ligands TNF and TRAIL and boosts effector caspase activation and subsequent apoptosis. Mechanistically, ASTX660 enhances amplification of death receptor‐generated apoptotic signals in a mitochondria‐dependent manner. Failure to activate the mitochondria‐associated (intrinsic) apoptosis pathway attenuated the apoptosis‐promoting effect of ASTX660. Further clinical studies are warranted to highlight the therapeutic potential of ASTX660 in colorectal cancer.

中文翻译：

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非拟肽 IAP 拮抗剂 ASTX660 使结直肠癌细胞对外源性细胞凋亡敏感

细胞凋亡抵抗会恶化癌症的治疗反应，并与不良预后相关。抑制抗凋亡蛋白可以恢复细胞死亡并提高治疗效果。cIAP1、cIAP2 和 XIAP 属于凋亡蛋白抑制剂 (IAP) 家族，可阻断细胞凋亡。用模拟细胞内源性 IAP 拮抗剂 SMAC（SMAC 模拟物）的 IAP 拮抗活性的肽或模拟肽来靶向 IAP，显示出有希望的结果，并促进了新型化合物的开发。ASTX660属于最近推出的一类非拟肽IAP拮抗剂，并已成功完成I期临床试验。然而，ASTX660 迄今为止仅在少数癌症实体中进行了评估。在这里，我们证明 ASTX660 在结直肠癌中具有促进细胞死亡的活性，并与临床上最先进的拟肽 IAP 拮抗剂 birinapant 进行了头对头比较。ASTX660 在死亡配体 TNF 和 TRAIL 刺激下促进外源性细胞凋亡途径的激活，并促进效应 caspase 激活和随后的细胞凋亡。从机制上讲，ASTX660 以线粒体依赖性方式增强死亡受体产生的细胞凋亡信号的放大。未能激活线粒体相关（内在）凋亡途径会减弱 ASTX660 的凋亡促进作用。需要进一步的临床研究来强调 ASTX660 在结直肠癌中的治疗潜力。