Table_2_Efficacy of a Novel Bi-Steric mTORC1 Inhibitor in Models of B-Cell Acute Lymphoblastic Leukemia.pdf

The mechanistic target of rapamycin (mTOR) is a kinase whose activity is elevated in hematological malignancies. mTOR-complex-1 (mTORC1) phosphorylates numerous substrates to promote cell proliferation and survival. Eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) are mTORC1 substrates with an integral role in oncogenic protein translation. Current pharmacological approaches to inhibit mTORC1 activity and 4E-BP phosphorylation have drawbacks. Recently we described a series of bi-steric compounds that are potent and selective inhibitors of mTORC1, inhibiting 4E-BP phosphorylation at lower concentrations than mTOR kinase inhibitors (TOR-KIs). Here we report the activity of the mTORC1-selective bi-steric inhibitor, RMC-4627, in BCR-ABL-driven models of B-cell acute lymphoblastic leukemia (B-ALL). RMC-4627 exhibited potent and selective inhibition of 4E-BP1 phosphorylation in B-ALL cell lines without inhibiting mTOR-complex-2 (mTORC2) activity. RMC-4627 suppressed cell cycle progression, reduced survival, and enhanced dasatinib cytotoxicity. Compared to a TOR-KI compound, RMC-4627 was more potent, and its effects on cell viability were sustained after washout in vitro. Notably, a once-weekly, well tolerated dose reduced leukemic burden in a B-ALL xenograft model and enhanced the activity of dasatinib. These preclinical studies suggest that intermittent dosing of a bi-steric mTORC1-selective inhibitor has therapeutic potential as a component of leukemia regimens, and further study is warranted.

雷帕霉素靶点（mTOR）是一种激酶，其在血液恶性肿瘤中的活性升高。mTOR复合体1（mTORC1）通过磷酸化众多底物以促进细胞增殖和存活。真核起始因子4E（eIF4E）结合蛋白（4E-BPs）是mTORC1的底物，在致癌蛋白翻译中起着至关重要的作用。目前抑制mTORC1活性和4E-BP磷酸化的药物治疗方法存在不足。近期，我们描述了一系列双酯化合物，这些化合物是mTORC1的强效且选择性的抑制剂，其抑制4E-BP磷酸化的浓度低于mTOR激酶抑制剂（TOR-KIs）。在此，我们报告了mTORC1选择性双酯抑制剂RMC-4627在BCR-ABL驱动型B细胞急性淋巴细胞白血病（B-ALL）模型中的活性。RMC-4627在B-ALL细胞系中表现出对4E-BP1磷酸化的强效且选择性抑制，而不会抑制mTOR复合体2（mTORC2）的活性。RMC-4627抑制细胞周期进展，降低生存率，并增强达沙替尼的细胞毒性。与TOR-KI化合物相比，RMC-4627的效力更强，其细胞活力影响在体外洗脱后仍持续存在。值得注意的是，每周一次、耐受性良好的剂量在B-ALL异种移植模型中降低了白血病负担，并增强了达沙替尼的活性。这些前期研究结果提示，间歇性给药的双酯mTORC1选择性抑制剂作为白血病治疗方案的一部分具有治疗潜力，进一步的研究是必要的。