Gamitrinib TPP is a Gamitrinib (GA) mitochondrial matrix inhibitor[1]. Gamitrinib TPP is a mitochondrial-targeted HSP90 inhibitor with anticancer activity used to chemically interfere with mitochondrial protein folding and induce mitophagy[2, 3].
In vitro, Gamitrinib TPP (10μM) treatment of HeLa cells stably expressing EGFP-Parkin for 4h and 8h induced Parkin (an E3 ubiquitin ligase) translocation in a time-dependent manner, induced mitophagy, and increased NP40 and SDS-insoluble proteins in mitochondria[4]. Gamitrinib TPP (15-20μM) treatment of glioblastoma cell lines (LN229, U251, U87 cells) for 16h concentration-dependently inhibited cell viability and induced mitochondrial apoptosis and autophagy[5].
In vivo, Gamitrinib TPP (5mg/kg) treated with intraperitoneal injection for 3 weeks in mice bearing a human glioma xenograft model partially inhibited tumor growth, and combined treatment with OTX015 significantly inhibited tumor growth and caused tumor regression[6].
References:
[1] Kang B H, Siegelin M D, Plescia J, et al. Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer[J]. Clinical Cancer Research, 2010, 16(19): 4779-4788.
[2] Wei S, Yin D, Yu S, et al. Antitumor activity of a mitochondrial-targeted HSP90 inhibitor in gliomas[J]. Clinical Cancer Research, 2022, 28(10): 2180-2195.
[3] Hayat U, Elliott G T, Olszanski A J, et al. Feasibility and safety of targeting mitochondria for cancer therapy–preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor[J]. Cancer biology & therapy, 2022, 23(1): 117-126.
[4] Fiesel F C, James E D, Hudec R, et al. Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy[J]. Oncotarget, 2017, 8(63): 106233.
[5] Siegelin M D, Dohi T, Raskett C M, et al. Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells[J]. The Journal of clinical investigation, 2011, 121(4): 1349-1360.
[6] Ishida C T, Shu C, Halatsch M E, et al. Mitochondrial matrix chaperone and c-myc inhibition causes enhanced lethality in glioblastoma[J]. Oncotarget, 2017, 8(23): 37140.
Gamitrinib TPP是一种Gamitrinib（GA）线粒体基质抑制剂[1]。Gamitrinib TPP是一种线粒体靶向HSP90抑制剂，具有抗癌活性，用于化学干扰线粒体蛋白质折叠并诱导线粒体自噬诱导[2, 3]。
在体外，Gamitrinib TPP（10μM）处理稳定表达EGFP-Parkin的HeLa细胞4h和8h，时间依赖性地诱导了Parkin（一种E3泛素连接酶）易位，诱导了线粒体自噬，增加了细胞线粒体中NP40和SDS不溶性蛋白[4]。Gamitrinib TPP（15-20 μM）处理胶质母细胞瘤细胞系（LN229、U251、U87细胞）16h，浓度依赖性地抑制了细胞活力，诱导了线粒体凋亡和自噬[5]。
在体内，Gamitrinib TPP（5mg/kg）通过腹腔注射治疗人类神经胶质瘤异种移植模型小鼠3周，部分抑制了肿瘤生长，与OTX015联合治疗显著抑制了肿瘤生长，并引起肿瘤消退[6]。