Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation. We developed a more synthetically tractable cysteine-reactive covalent ligand, JNS 1-40, that selectively targets C377 of PPP2R1A to impair breast cancer signaling, proliferation, andin vivotumor growth. Our study highlights the utility of using chemoproteomics to map druggable hotspots targeted by complex natural products and subsequently interrogating these sites with more synthetically tractable covalent ligands for cancer therapy.

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针对抗癌天然产物靶向的可药用热点的共价配体发现

许多表现出治疗活性的天然产物通常难以合成或分离并且具有未知的靶标，从而阻碍了它们作为药物的开发。鉴定以共价作用的抗癌天然产物为靶点的可药物热点，可以使这些部位与可合成的化合物更容易地进行药理学研究。在这里，我们使用化学代谢组学平台发现了具有aferin A的抗癌天然产物将C377靶向肿瘤抑制蛋白磷酸酶2A（PP2A）复合物的调节亚基PPP2R1A，从而导致PP2A活性激活，AKT失活和乳房受损癌细胞增殖。我们开发了一种更具合成易处理性的半胱氨酸反应性共价配体JNS 1-40，可选择性地靶向PPP2R1A的C377来削弱乳腺癌的信号传导，增殖，和体内肿瘤生长。我们的研究强调了使用化学蛋白质组学绘制复杂天然产物靶向的可药物热点的实用性，然后用更具合成易处理性的共价配体对这些部位进行查询的方法，以用于癌症治疗。