Hybrid molecule between platanic acid and LCL-161 as a yes-associated protein degrader
Hybrid molecule between platanic acid and LCL-161 as a yes-associated protein degrader
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铂酸和 LCL-161 之间的混合分子作为 yes 相关蛋白降解剂
DOI：
10.1093/jb/mvac021
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Itoh Susumu
中科院分区：
文献类型：
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作者：
Nakano Naoko;Fukuda Kazuo;Tashiro Etsu;Ishikawa Haruka;Nagano Waka;Kawamoto Rie;Mori Alice;Watanabe Misao;Yamazaki Ryu;Nakane Takahisa;Naito Mikihiko;Okamoto Iwao;Itoh Susumu
异常调节的yes相关蛋白（雅普）参与多种恶性肿瘤。然而，发现可药用的雅普抑制剂是困难的，因为雅普本身不具有任何酶活性。在这种情况下，基于结合靶蛋白和E3泛素连接酶的杂合分子的靶蛋白降解策略可用于抑制表现出异常活化和/或过度表达的蛋白。在筛选与YAP相互作用的小分子化合物后，我们鉴定了一种铂酸HK 13作为与雅普相互作用的新型化合物。接下来，我们合成了铂酸和LCL-161的杂合化合物，据报道该化合物对E3遍在蛋白连接酶之一cIAP表现出高亲和力。在这些化合物中，HK 24具有抑制过表达雅普的NCI-H290细胞生长的能力。这种抑制活性可能是由雅普降解介导的，尽管HK 24表现出弱的雅普降解。此外，我们通过在蛋白酶体抑制剂存在下培养NCI-H290细胞，证实了蛋白酶体途径参与了HK 24依赖性雅普降解。因此，铂酸可能是靶向雅普的分子药物的潜在候选者。
Dysregulated yes-associated protein (YAP) is involved in several malignant cancers. However, discovering a druggable YAP inhibitor(s) is difficult because YAP itself does not have any enzymatic activity. In such cases, targeted protein degradation strategies based on hybrid molecules that bind to the target protein and an E3 ubiquitin ligase are useful for suppressing proteins that exhibit aberrant activation and/or excessive expression. Upon screening YAP-interacting small compounds, we identified HK13, a platanic acid, as a novel compound that interacts with YAP. Next, we synthesized hybrid compounds of platanic acid and LCL-161, which reportedly shows a high affinity for cIAP, one of E3 ubiquitin ligases. Among these compounds, HK24 possessed the ability to inhibit the growth of YAP overexpressing NCI-H290 cells. This inhibitory activity may be mediated by YAP degradation, although HK24 exhibited weak YAP degradation. Furthermore, we confirmed involvement of proteasome pathway in HK24-dependent YAP degradation by culturing NCI-H290 cells in the presence of a proteasome inhibitor. Therefore, it is possible that platanic acid is a potential candidate for molecular medicine targeting YAP.