Inhibitors of apoptosis proteins (IAPs) are validated onco-targets, as their overexpression correlates with cancer onset, progression, diffusion and chemoresistance. IAPs regulate cell death survival pathways, inflammation, and immunity. Targeting IAPs, by impairing their protein-protein interaction surfaces, can affect events occurring at different stages of cancer development.

To this purpose, we employed a rational virtual screening approach to identify compounds predicted to interfere with the assembly of pro-survival macromolecular complexes. One of the candidates, FC2, was shown to bind in vitro the BIR1 domains of both XIAP and cIAP2. Moreover, we demonstrated that FC2 can induce cancer cell death as a single agent and, more potently, in combination with the Smac-mimetic SM83 or with the cytokine TNF. FC2 determined a prolonged activation of the NF-κB pathway, accompanied to a stabilization of XIAP-TAB1 complex. This candidate molecule represents a valuable lead compound for the development of a new class of IAP-antagonists for cancer treatment.

凋亡蛋白 (IAP) 抑制剂是经过验证的肿瘤靶点，因为它们的过度表达与癌症的发生、进展、扩散和化学抗性相关。IAP 调节细胞死亡存活途径、炎症和免疫。靶向 IAP，通过损害它们的蛋白质-蛋白质相互作用表面，可以影响发生在癌症发展不同阶段的事件。

为此，我们采用了一种合理的虚拟筛选方法来识别预测会干扰促存活大分子复合物组装的化合物。其中一个候选物 FC2 显示在体外结合XIAP 和 cIAP2 的 BIR1 域。此外，我们证明 FC2 可以作为单一试剂诱导癌细胞死亡，并且与 Smac 模拟物 SM83 或细胞因子 TNF 联合使用更有效。FC2 确定了 NF-κB 通路的延长激活，伴随着 XIAP-TAB1 复合物的稳定。这种候选分子代表了一种有价值的先导化合物，可用于开发一类用于癌症治疗的新型 IAP 拮抗剂。