ArticleTargeted oncology2019
Absorption, Distribution, and Binding Profile of ME-401, a Potent and Selective Oral Small-Molecule Inhibitor of Phosphatidylinositol 3-Kinase δ (PI3Kδ) in Animal and B-Cell Lymphoma Models.
Article in Targeted oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial.Nature communications · 2026Article
- The Development of Novel Therapies for Chronic Lymphocytic Leukaemia in the Era of Targeted Drugs.Journal of clinical medicine · 2025Review
- Fluorinated small molecule derivatives in cancer immunotherapy: emerging frontiers and therapeutic potential.Frontiers in immunology · 2025Review
- A long-lasting PI3Kδ inhibitor zandelisib forms a water-shielded hydrogen bond with p110δ and demonstrates sustained inhibitory effects.American journal of cancer research · 2025Article
- The PI3Kδ inhibitor zandelisib on intermittent dosing in relapsed/refractory follicular lymphoma: Results from a global phase 2 study.HemaSphere · 2024Article
- Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas.British journal of haematology · 2024Article
- Zandelisib (ME-401) in Japanese patients with relapsed or refractory indolent non-Hodgkin's lymphoma: an open-label, multicenter, dose-escalation phase 1 study.International journal of hematology · 2022Article
- Zandelisib with continuous or intermittent dosing as monotherapy or in combination with rituximab in patients with relapsed or refractory B-cell malignancy: a multicentre, first-in-patient, dose-escalation and dose-expansion, phase 1b trial.The Lancet. Oncology · 2022Article
- Therapeutic strategies of glioblastoma (GBM): The current advances in the molecular targets and bioactive small molecule compounds.Acta pharmaceutica Sinica. B · 2022Review
- PI3K Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Current Status and Future Perspectives.Cancers · 2022Review
- Current and future treatment strategies in chronic lymphocytic leukemia.Journal of hematology & oncology · 2021Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPhosphatidylinositol 3-kinase isoform δ (PI3Kδ) mediates multiple events in lymphocytes, including cell proliferation, survival, and motility. Inhibition of PI3Kδ, with downstream inhibitory effects on cell growth and survival, has been utilized to treat lymphoid malignancies. ME-401 is an oral, once-daily, selective PI3Kδ inhibitor with an optimized pharmacologic profile that is in clinical development for the treatment of B-cell malignancies.
objectivesThis work examined aspects of the pharmacologic profile of ME-401 in preclinical models to investigate the basis of the clinical activity of ME-401 that may differentiate it from other currently approved PI3Kδ inhibitors.
methodsWe determined the ME-401 blood to plasma ratios, permeability, and purified enzyme-binding kinetics. The oral bioavailability and volume of distribution of ME-401 were evaluated in various species. ME-401 concentrations in plasma and tumor and brain tissues were evaluated following oral administration in an A20 syngeneic mouse model of B-cell lymphoma. Idelalisib was used as a reference compound for the measurement of purified enzyme-binding kinetics and concentrations in plasma and tumor in the A20 syngeneic mouse model.
resultsOral administration of ME-401 to dogs resulted in 79% bioavailability compared with intravenous administration. Allometric scaling from rodents, dogs, and nonhuman primates resulted in a predicted human volume of distribution at steady state of 10.75 L/kg. ME-401 was shown to distribute into the lymph in dogs and permeate into cells readily, with a human blood to plasma ratio of 1.4 and ~ 50% retention in the Caco-2 cell monolayer at 1 μM. The high binding affinity and low dissociation rate of ME-401 resulted in an equilibrium dissociation constant (K
conclusionsThese data support the capacity of ME-401 to be orally absorbed, distribute to target tissues, enter and accumulate in target cells, and bind to the target with high affinity to exert its mechanism of action. These characteristics underlie the high clinical potency seen in B-cell malignancies that may differentiate ME-401 from other PI3Kδ inhibitors currently approved or in development.
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