The clinical benefits of pan-mTOR active-site inhibitors are limited by toxicity and relief of feedback inhibition of receptor expression. To address these limitations, we designed a series of compounds that selectively inhibit mTORC1 and not mTORC2. These ‘bi-steric inhibitors’ comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. Structural modification of these components modulated their affinities for their binding sites on mTOR and the selectivity of the bi-steric compound. mTORC1-selective compounds potently inhibited 4EBP1 phosphorylation and caused regressions of breast cancer xenografts. Inhibition of 4EBP1 phosphorylation was sufficient to block cancer cell growth and was necessary for maximal antitumor activity. At mTORC1-selective doses, these compounds do not alter glucose tolerance, nor do they relieve AKT-dependent feedback inhibition of HER3. Thus, in preclinical models, selective inhibitors of mTORC1 potently inhibit tumor growth while causing less toxicity and receptor reactivation as compared to pan-mTOR inhibitors.

pan-mTOR 活性位点抑制剂的临床益处受限于毒性和缓解受体表达的反馈抑制。为了解决这些限制，我们设计了一系列选择性抑制 mTORC1 而不是 mTORC2 的化合物。这些“双空间抑制剂”包含与 mTOR 活性位点抑制剂共价连接的雷帕霉素样核心部分。这些成分的结构修饰调节了它们对 mTOR 结合位点的亲和力和双立体化合物的选择性。mTORC1 选择性化合物有效抑制 4EBP1 磷酸化并导致乳腺癌异种移植物消退。抑制 4EBP1 磷酸化足以阻止癌细胞生长，并且是最大抗肿瘤活性所必需的。在 mTORC1 选择性剂量下，这些化合物不会改变葡萄糖耐量，它们也不能减轻 HER3 的 AKT 依赖性反馈抑制。因此，在临床前模型中，与泛 mTOR 抑制剂相比，mTORC1 的选择性抑制剂可有效抑制肿瘤生长，同时引起较少的毒性和受体再激活。