Mubritinib (TAK 165)

Mubritinib (TAK-165, CAS No. 366017-09-6) has its core target on mitochondrial electron transport chain complex I (ETC Complex I, NADH dehydrogenase). It inhibits the function of the complex by binding to its active site in a ubiquinone-dependent manner. Meanwhile, it can suppress the binding of the latency-associated nuclear antigen (LANA) protein of Kaposi’s sarcoma-associated herpesvirus (KSHV) to viral terminal repeat (TR) sequences. The originally reported target HER2 has no actual functional relevance in diseases such as acute myeloid leukemia (AML) and primary effusion lymphoma (PEL). Its key concentration data are clearly defined: the in vitro IC₅₀ for complex I inhibition is 51 nM (cell-free assay); the median GI₅₀ in AML cells is 374 nM (147–153 nM for the MLL-AF9 subtype); the GI₅₀ in KSHV-positive PEL cells ranges from 7.5 to 17.1 nM (7.5 nM in BC1 cells, 13.45 nM in BC3 cells, 17.1 nM in BCBL1 cells); the original IC₅₀ for HER2 inhibition is 0.35 μM, which has no clinical relevance.

Commonly used application concentrations are as follows: in in vitro cell assays, 0.1–10 μM for AML cells, 7.5–15 nM for PEL cells, and nanomolar range (10–100 nM) for complex I inhibition assays; in animal experiments, 20–25 mg/kg/day via intraperitoneal injection or oral administration. The therapeutically effective concentration corresponds to preclinical dosing regimens: oral administration of 20 mg/kg (AML model) or 25 mg/kg (PEL model) in mice can maintain the serum concentration at an effective level for 48 consecutive hours. Mubritinib was previously used in Phase I clinical trials for solid tumors, and is now proposed to be repurposed for chemotherapy-resistant AML and PEL, with a recommended reference dose of 20–25 mg/kg once daily. Its biological activities are manifested as inhibiting oxidative phosphorylation (OXPHOS), inducing oxidative stress and apoptosis, and selectively killing chemotherapy-resistant AML cells (subtypes with high HOX gene expression or NPM1/FLT3/DNMT3A mutations) as well as PEL cells, without affecting normal CD34⁺ hematopoietic stem cells. It exhibits good tolerability in animal experiments and can significantly prolong the survival time of tumor-bearing mice.

References:

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