{"doi":"10.3389/fonc.2021.673213","title":"Efficacy of a Novel Bi-Steric mTORC1 Inhibitor in Models of B-Cell Acute Lymphoblastic Leukemia","abstract":"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.","journal":"Frontiers in Oncology","year":2021,"id":179658,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":407572,"name":"Sharmila Mallya","orcid":"0000-0002-7135-6536","position":1,"is_corresponding":false},{"id":727969,"name":"Nuntana Dinglasan","orcid":null,"position":2,"is_corresponding":false},{"id":408337,"name":"Amos Fung","orcid":null,"position":3,"is_corresponding":false},{"id":333843,"name":"Tram Nguyen","orcid":"0000-0002-4846-2947","position":4,"is_corresponding":false},{"id":407571,"name":"Lee-or Herzog","orcid":"0000-0001-6255-5317","position":5,"is_corresponding":false},{"id":727970,"name":"Joshua Thao","orcid":null,"position":6,"is_corresponding":false},{"id":727971,"name":"Edward Lorenzana","orcid":null,"position":7,"is_corresponding":false},{"id":333840,"name":"David Wildes","orcid":"0009-0009-3855-7270","position":8,"is_corresponding":false},{"id":333844,"name":"Mallika Singh","orcid":"0009-0003-0234-1589","position":9,"is_corresponding":false},{"id":333847,"name":"Jacqueline A.M. Smith","orcid":"0000-0001-5028-8725","position":10,"is_corresponding":false},{"id":235177,"name":"David A. Fruman","orcid":"0000-0002-1796-5162","position":11,"is_corresponding":false},{"id":727329,"name":"Bianca J. Lee","orcid":"0009-0000-4888-8684","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-18T23:47:48.974996Z","pmid":"34408976","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}