Characterization of TR-107, a novel chemical activator of the human mitochondrial protease ClpP.
Characterization of TR-107, a novel chemical activator of the human mitochondrial protease ClpP.
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DOI：
10.1002/prp2.993
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发表时间：
2022-08
影响因子：
2.6
通讯作者：
Graves, Lee M.
中科院分区：
文献类型：
--
作者：
Fennell, Emily M. J.;Aponte-Collazo, Lucas J.;Wynn, Joshua D.;Drizyte-Miller, Kristina;Leung, Elisa;Greer, Yoshimi Endo;Graves, Paul R.;Iwanowicz, Andrew A.;Ashamalla, Hani;Holmuhamedov, Ekhson;Lang, Henk;Karanewsky, Donald S.;Der, Channing J.;Houry, Walid A.;Lipkowitz, Stanley;Iwanowicz, Edwin J.;Graves, Lee M.
关键词：
我们最近描述了一类新的线粒体蛋白酶ClpP小分子激活剂的鉴定。Madera Therapeutics合成的这些化合物显示出比相关化合物ONC201更强的肿瘤生长抑制效力。在这项研究中，我们描述了下一代高效和选择性小分子ClpP激活剂（TR化合物）的化学优化和表征，并在体外和体内证明了它们对乳腺癌模型的有效性。我们选择了一种具有优异效价、特异性和药物样特性的化合物（TR‐107）进行进一步评价。在三阴性乳腺癌（TNBC）细胞模型中，TR - 107在低纳摩尔范围内显示出ClpP依赖性的生长抑制作用，与紫杉醇具有同等效力。TR‐107还以时间、剂量和ClpP依赖性的方式降低了特定的线粒体蛋白，包括OXPHOS和TCA循环成分。海马XF分析和葡萄糖剥夺实验证实，TR‐107暴露后，OXPHOS失活，对糖酵解的依赖性增加。将TR‐107的药代动力学性质与其他已知的ClpP激活剂（包括ONC201和ONC212）进行比较。TR‐107在口服给药后表现出良好的暴露和血清t1 /2。使用人TNBC MDA‐MB‐231异种移植物，研究了TR‐107的抗肿瘤反应。与对照小鼠相比，口服TR - 107可减少肿瘤体积，延长生存期。通过TFAM和其他线粒体蛋白的免疫印迹验证了ClpP在体内的激活。总之，我们描述了高效的新型ClpP激动剂的鉴定，通过靶向灭活OXPHOS和破坏线粒体代谢，提高了对TNBC的疗效。检测线粒体ClpP激活和结合的化合物，有效抑制乳腺癌细胞生长。TR107选择和检查针对多个线粒体参数。MDA - MB - 231异种移植模型显示TR107肿瘤消退的效果。
We recently described the identification of a new class of small‐molecule activators of the mitochondrial protease ClpP. These compounds synthesized by Madera Therapeutics showed increased potency of cancer growth inhibition over the related compound ONC201. In this study, we describe chemical optimization and characterization of the next generation of highly potent and selective small‐molecule ClpP activators (TR compounds) and demonstrate their efficacy against breast cancer models in vitro and in vivo. We selected one compound (TR‐107) with excellent potency, specificity, and drug‐like properties for further evaluation. TR‐107 showed ClpP‐dependent growth inhibition in the low nanomolar range that was equipotent to paclitaxel in triple‐negative breast cancer (TNBC) cell models. TR‐107 also reduced specific mitochondrial proteins, including OXPHOS and TCA cycle components, in a time‐, dose‐, and ClpP‐dependent manner. Seahorse XF analysis and glucose deprivation experiments confirmed the inactivation of OXPHOS and increased dependence on glycolysis following TR‐107 exposure. The pharmacokinetic properties of TR‐107 were compared with other known ClpP activators including ONC201 and ONC212. TR‐107 displayed excellent exposure and serum t 1/2 after oral administration. Using human TNBC MDA‐MB‐231 xenografts, the antitumor response to TR‐107 was investigated. Oral administration of TR‐107 resulted in a reduction in tumor volume and extension of survival in the treated compared with vehicle control mice. ClpP activation in vivo was validated by immunoblotting for TFAM and other mitochondrial proteins. In summary, we describe the identification of highly potent new ClpP agonists with improved efficacy against TNBC, through targeted inactivation of OXPHOS and disruption of mitochondrial metabolism. Compounds tested for mitochondrial ClpP activation and binding, potent inhibition of breast cancer cell growth. TR107 selected and examined against multiple mitochondrial parameters. Efficacy of tumor regression by TR107 shown using MDA‐MB‐231 xenograft model.
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DOI：
10.1016/j.bbamcr.2011.06.007
发表时间：
2012-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Baker TA;Sauer RT
通讯作者：
Sauer RT
影响因子：
--
作者：
Chae YK;Arya A;Malecek MK;Shin DS;Carneiro B;Chandra S;Kaplan J;Kalyan A;Altman JK;Platanias L;Giles F
通讯作者：
Giles F
影响因子：
7.3
作者：
Ishizawa J;Kojima K;Chachad D;Ruvolo P;Ruvolo V;Jacamo RO;Borthakur G;Mu H;Zeng Z;Tabe Y;Allen JE;Wang Z;Ma W;Lee HC;Orlowski R;Sarbassov dos D;Lorenzi PL;Huang X;Neelapu SS;McDonnell T;Miranda RN;Wang M;Kantarjian H;Konopleva M;Davis RE;Andreeff M
通讯作者：
Andreeff M
影响因子：
4
作者：
Graves, Paul R.;Aponte-Collazo, Lucas J.;Graves, Lee M.
通讯作者：
Graves, Lee M.
影响因子：
3.3
作者：
Jacques, Samuel;van der Sloot, Almer M.;Tyers, Mike
通讯作者：
Tyers, Mike