IMT1B (LDC203974) 是一种具有口服活性的，非竞争性的，特异性的线粒体 RNA 聚合酶 (POLRMT) 别构抑制剂，可抑制线粒体 DNA (mtDNA) 的表达。IMT1B 具有抗肿瘤作用。
IMT1B (LDC203974) is an orally active, noncompetitive and specific allosteric inhibitor of mitochondrial RNA polymerase (POLRMT) and inhibits mitochondrial DNA (mtDNA) expression. IMT1B has anti-tumour effects[1].
IMT1B is a noncompetitive inhibitor that causes a conformational change of POLRMT, which blocks substrate binding and transcription in a dose-dependent way in vitro[1].IMT1B (0.01 nM-10 μM; 72-168 hours) dose-dependently decreases in cell viability in A2780, A549 and HeLa cells[1].IMT1B depletes cellular metabolites[1].IMT1B increases the levels of mono- and diphosphate nucleotides that results in a considerable increase in the AMP/ATP ratio and levels of phosphorylated AMPK[1].
IMT1B (100 mg/kg; p.o.; daily; for four weeks) significantly reduces tumour size in mice containing xenografts[1].IMT1B reduces mtDNA transcript levels and respiratory-chain subunit levels in tumours[1].IMT1B exhibits good oral bioavailability (mice 101 %) and Cmax (mice 5149 ng/mL) following oral administration (mice 10 mg/kg)[1].IMT1B exhibits elimination half-life (mice 1.88 h) due to plasma clearance (mice 0.44 L/h/kg) following intravenous administration (mice 1 mg/kg)[1].
[1]. Nina A Bonekamp, et al. Small-molecule inhibitors of human mitochondrial DNA transcription. Nature. 2020 Dec;588(7839):712-716.
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