IMT1B is a highly specific inhibitor of mitochondrial RNA polymerase (POLRMT), inhibiting mitochondrial gene expression[1]. IMT1B dose-dependently reduces mitochondrial DNA transcription levels, leading to dysfunction of OXPHOS protein complexes and cellular energy crisis, inhibiting a variety of cancer cells [2]. IMT1B has been widely used in cell models to regulate mitochondrial DNA transcription for altering the sensitivity to radiotherapy[3].
In vitro, IMT1B treatment for 168 hours significantly inhibited the proliferation of A2780, MDA-MB-468 and HeLa cells, and the IC50 values were 0.138 ± 0.015, 0.189 ± 0.015, and 1.052 ± 0.154μM, respectively[4]. The 72-hour treatment with 1µM IMT1B increased the sensitivity of chemo-resistant HCT116 cells to 5-fluorouracil, inhibited mitochondrial DNA transcription in the cells, without affecting the expression level of HOXC11[5]. IMT1B treatment at 2.5µM for 24 hours significantly reduced the phosphorylation levels of IRF3 and STAT1 in wild-type A375 cells induced by caspase-independent cell death, and inhibited the expression of ISG15 and IFIT3 transcripts[6]. 0.2µM of IMT1B pretreatment for 1 hour can effectively reduce the dsRNA level in nucleus pulposus cells, decrease the levels of CCL2/7 in the cells, and down-regulate the expressions of p-PKR/PKR, p-eIF2α/eIF2α and ATF4[7].
In vivo, IMT1B treatment (100mg/kg; p.o.) for 27 days could significantly reduce the tumor volume in a xenograft mouse model of A2780 cells, and decrease the mitochondrial DNA transcription level as well as the expression level of respiratory chain subunits in the tumors[1]. In the mouse model of liver ischemia-reperfusion injury, a single intravenous injection of 1mg/kg IMT1B for 24 hours significantly resulted in a significant decrease in the necrotic area of liver tissue in mice, accompanied by a decrease in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels[8].
References:
[1] Bonekamp N A, Peter B, Hillen H S, et al. Small-molecule inhibitors of human mitochondrial DNA transcription[J]. Nature, 2020, 588(7839): 712-716.
[2] Yu H J, Xiao G L, Zhao Y Y, et al. Targeting mitochondrial metabolism and RNA polymerase POLRMT to overcome multidrug resistance in cancer[J]. Frontiers in Chemistry, 2021, 9: 775226.
[3] Li G, Lin X, Wang X, et al. Enhancing radiosensitivity in triple-negative breast cancer through targeting ELOB[J]. Breast Cancer, 2024, 31(3): 426-439.
[4] Li X, Ze X, Zhou S, et al. Discovery of a novel, potent, orally active, and safe inhibitor targeting human mitochondrial RNA polymerase[J]. Journal of Medicinal Chemistry, 2023, 66(7): 5118-5153.
[5] Chu S, Ren X, Cao L, et al. HOXC11-mediated regulation of mitochondrial function modulates chemoresistance in colorectal cancer[J]. BMC cancer, 2024, 24(1): 921.
[6] Killarney S T, Washart R, Soderquist R S, et al. Executioner caspases restrict mitochondrial RNA-driven Type I IFN induction during chemotherapy-induced apoptosis[J]. Nature Communications, 2023, 14(1): 1399.
[7] Tian S, Chen X, Wu W, et al. Nucleus pulposus cells regulate macrophages in degenerated intervertebral discs via the integrated stress response-mediated CCL2/7-CCR2 signaling pathway[J]. Experimental & molecular medicine, 2024, 56(2): 408-421.
[8] Wu C, Miao H, Yi Z, et al. STING-mediated mitochondrial DNA release exacerbates PANoptosis in liver ischemia reperfusion injury[J]. International Immunopharmacology, 2025, 157: 114778.