Novel Inhibitors Induce Large Conformational Changes of GAB1 Pleckstrin Homology Domain and Kill Breast Cancer Cells

The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein.

Grb2 相关联结合蛋白 1（GAB1）整合来自不同信号通路的信号，并在多种癌症中表达过度，因此成为了一种新的治疗靶点。在本研究中，我们旨在针对 GAB1 的 Pleckstrin 同源结构域（PH）进行癌症治疗。通过我们所构建的同源模型，对五百万个化合物进行的高通量虚拟筛选产生了五个与 GAB1 PH 结构域表现出强结合亲和力的候选分子。我们对于配体结合亲和力的预测也与实验测得的 KD 值相吻合。此外，分子动力学研究表明，GAB1 PH 结构域在配体结合后发生了显著的构象变化。进一步地，这些候选分子抑制了 GAB1 的磷酸化，并对 MDA-MB-231 和 T47D 乳腺癌细胞系展现出强大的、肿瘤特异性细胞毒性。这一努力标志着首次发现具有针对 GAB1 PH 结构域的同类抑制剂，具有针对乳腺癌治疗的潜力，并为基于结构的靶向蛋白治疗方法提供了新的见解。