Lee Bianca J, Mallya Sharmila, Dinglasan Nuntana, Fung Amos, Nguyen Tram, Herzog Lee-Or, Thao Joshua, Lorenzana Edward G, Wildes David, Singh Mallika, Smith Jacqueline A M, Fruman David A
Department of Biology, Revolution Medicines, Inc., Redwood City, CA, United States.
Department of Molecular Biology & Biochemistry, University of California, Irvine, CA, United States.
Front Oncol. 2021 Aug 2;11:673213. doi: 10.3389/fonc.2021.673213. eCollection 2021.
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 . 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.
雷帕霉素的作用靶点（mTOR）是一种激酶，其活性在血液系统恶性肿瘤中升高。mTOR复合物1（mTORC1）使众多底物磷酸化，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底物，在致癌蛋白翻译中起不可或缺的作用。目前抑制mTORC1活性和4E-BP磷酸化的药理学方法存在缺陷。最近，我们描述了一系列双位点化合物，它们是mTORC1的强效和选择性抑制剂，在比mTOR激酶抑制剂（TOR-KIs）更低的浓度下就能抑制4E-BP磷酸化。在此，我们报告mTORC1选择性双位点抑制剂RMC-4627在B细胞急性淋巴细胞白血病（B-ALL）的BCR-ABL驱动模型中的活性。RMC-4627在B-ALL细胞系中对4E-BP1磷酸化表现出强效和选择性抑制，而不抑制mTOR复合物2（mTORC2）的活性。RMC-4627抑制细胞周期进程，降低存活率，并增强达沙替尼的细胞毒性。与一种TOR-KI化合物相比，RMC-4627更有效，且洗脱后其对细胞活力的影响仍持续存在。值得注意的是，每周一次、耐受性良好的剂量可降低B-ALL异种移植模型中的白血病负担，并增强达沙替尼的活性。这些临床前研究表明，间歇性给予双位点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，值得进一步研究。
