AKT is a serine/threonine kinase that is essential for cellular metabolism and proliferation and is overactive in cancer cells. Small molecule catalytic inhibitors of all three AKT isoforms, as well as selective AKT degraders, have been developed, but the therapeutic efficacy of these compounds remains less than optimal. In particular, existing AKT degraders such as INY-03-041 elicit slow degradation kinetics despite improved potency over catalytic inhibitors. Erickson et al. designed a second-generation AKT degrader called INY-05-040, which rapidly degraded AKT protein and showed sustained reduction of AKT and downstream signaling relative to the first-generation degrader. Consistent with the improved efficacy, treatment with INY-05-040 also decreased cell growth in multiple breast cancer cell lines. Transcriptomic and metabolomic analysis of cells treated with INY-05-040 versus the small molecule inhibitor GDC-0068 revealed similarities in downstream gene and metabolic signatures, but also distinct clusters. To further elucidate these differences, a computational method called COSMOS (Causal Oriented Search of Multi-Omics Space) that integrated the transcriptomic and metabolomic datasets was utilized, revealing that degradation of AKT specifically induces activation of the stress mitogen-activated protein kinases (MAPKs) MAPK8 (JNK1) and MAPK14 (p38α), along with inflammatory signaling. Parallel studies analyzing the responsiveness to INY-05-040 in a panel of 288 cancer cell lines integrated with publicly accessible information from the Cancer Dependency map confirmed the COSMOS analysis, showing a positive correlation between sensitivity to INY-05-040 and JNK1 signaling. The findings from Erickson et al. reveal a potential workflow to identify novel downstream mediators that may distinguish the modes of action between small molecule-mediated inhibition versus degradation.

Original reference: Sci. Signal. https://doi.org/10.1126/scisignal.adf2670 (2024)

AKT 是一种丝氨酸/苏氨酸激酶，对于细胞代谢和增殖至关重要，并且在癌细胞中过度活跃。所有三种 AKT 亚型的小分子催化抑制剂以及选择性 AKT 降解剂均已开发出来，但这些化合物的治疗功效仍达不到最佳水平。特别是，现有的 AKT 降解剂（例如 INY-03-041）尽管比催化抑制剂的效力有所提高，但仍引起缓慢的降解动力学。埃里克森等人。设计了名为 INY-05-040 的第二代 AKT 降解剂，它能快速降解 AKT 蛋白，并且相对于第一代降解剂，AKT 和下游信号传导持续减少。与疗效的改善一致，INY-05-040 治疗还降低了多种乳腺癌细胞系的细胞生长。对用 INY-05-040 处理的细胞与小分子抑制剂 GDC-0068 处理的细胞进行转录组学和代谢组学分析，揭示了下游基因和代谢特征的相似性，但也存在不同的簇。为了进一步阐明这些差异，使用了一种名为 COSMOS（多组学空间因果导向搜索）的计算方法，该方法整合了转录组学和代谢组学数据集，揭示了 AKT 的降解特异性诱导应激丝裂原激活蛋白激酶 (MAPK) 的激活MAPK8 (JNK1) 和 MAPK14 (p38α)，以及炎症信号传导。平行研究分析了一组 288 个癌细胞系对 INY-05-040 的反应性，并与癌症依赖性图谱中的公开信息相结合，证实了 COSMOS 分析，显示对 INY-05-040 和 JNK1 信号传导的敏感性之间存在正相关。埃里克森等人的研究结果。揭示了识别新型下游介质的潜在工作流程，这些介质可以区分小分子介导的抑制与降解之间的作用模式。

原文参考： Sci.信号。 https://doi.org/10.1126/scisignal.adf2670（2024）