Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer.
Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer.
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DOI：
10.1021/acs.jmedchem.2c00190
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发表时间：
2022-07-14
影响因子：
7.3
通讯作者：
Muth A
中科院分区：
文献类型：
--
作者：
Kanabar D;Goyal M;Kane EI;Chavan T;Kabir A;Wang X;Shukla S;Almasri J;Goswami S;Osman G;Kokolis M;Spratt DE;Gupta V;Muth A
Gankyrin是一种癌蛋白，与多种癌症类型的发生有关。它调节多种肿瘤抑制蛋白(TSPs)在肝癌中的表达水平，然而，Gankyrin对这些TSPs在乳腺癌和肺癌中的调控还没有得到深入的研究。此外，还没有开发出小分子甘结蛋白抑制剂，它对过表达甘结蛋白的乳腺癌和肺癌具有强大的抗增殖活性。在此，我们报道了基于结构的甘草蛋白结合小分子的设计，该小分子在体外肿瘤模拟模型中有效地抑制了过表达A549和MDA-MB-231的甘草蛋白癌细胞的增殖，减少了克隆形成，并抑制了3D球体的生长。研究表明，Gankyrin的抑制作用是通过其三维结构的稳定或不稳定来实现的。这些研究阐明了甘草蛋白的小分子抑制机制，并证明甘草蛋白是治疗乳腺癌和肺癌的一个可行的治疗靶点。
Gankyrin is an oncoprotein responsible for the development of numerous cancer types. It regulates the expression levels of multiple tumor suppressor proteins (TSPs) in liver cancer, however, gankyrin’s regulation of these TSPs in breast and lung cancer has not been thoroughly investigated. Additionally, no small molecule gankyrin inhibitor has been developed which demonstrates potent antiproliferative activity against gankyrin overexpressing breast and lung cancers. Herein, we are reporting the structure-based design of gankyrin-binding small molecules which potently inhibited the proliferation of gankyrin overexpressing A549 and MDA-MB-231 cancer cells, reduced colony formation, and inhibited the growth of 3D spheroids in an in vitro tumor simulation model. Investigations demonstrated that gankyrin inhibition occurs through either stabilization or destabilization of its 3D structure. These studies shed light on the mechanism of small molecule inhibition of gankyrin and demonstrate that gankyrin is a viable therapeutic target for the treatment of breast and lung cancer.
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