MYLS22 is a selective inhibitor of optic atrophy 1 (OPA1). MYLS22 inhibits tumor growth by targeting endothelial OPA1 and inhibits angiogenesis by affecting NF-kB activity and angiogenic gene expression. It has anti-angiogenic and anti-cancer activities [1-7].
MYLS22 (50μM) inhibits the growth of PANC-1 cells after 2 days and reduces cell migration after 72 hours [1]. MYLS22 (30μM, 72h) restores gefitinib-induced mitochondrial apoptosis in PC9M2 cells [3]. MYLS22 (50μM, 48h) significantly increased doxorubicin-induced cell killing and reduced doxorubicin-mediated mitochondrial elongation and OXPHOS [4]. MYLS22 (50μM, 24h), by inhibiting OPA1, reverses TIM-4-induced enhancement of OXPHOS and disrupts mitochondrial fusion, thereby attenuating lung cancer progression [5].
In a subcutaneous B16F10 mouse melanoma mode using C57BL6/J mice, MYLS22 (10mg/kg, ip, 6d) effectively inhibited melanoma proliferation and growth [2]. In a subcutaneous PC9M2 xenograft model using KSN/Slc mice, MYLS22 (25mg/kg, po, 18d) reversed the resistance of lung adenocarcinoma cells to gefitinib in vivo, inhibited tumor proliferation and induced tumor cell death [3]. In an A549 xenograft tumor model using female athymic nude mice, MYLS22 (10mg/kg, ip, 18d) significantly enhanced the anticancer efficacy of BAY-876 [6]. In the MDA-MB-231 xenograft tumor model of female mice, MYLS22 (10mg/kg, ip, 18d) inhibited the growth of TNBC in mice by inhibiting tumor growth, invasiveness and neovascularization [7]. MYLS22 (0, 12.5, 25 and 50mg/kg) inhibited L-OPA1, resulting in more severe lung tissue damage in mice and upregulated the inflammatory cytokines total IL-1β, IL-1β p17 and NF-κB p65 in vivo. Among them, 12.5mg/kg MYLS22 was sufficient to cause severe lung damage and inflammation in mice [8].
References:
[1]. Murata D, Ito F, Tang G, et al. mCAUSE: Prioritizing mitochondrial targets that alleviate pancreatic cancer cell phenotypes[J]. iScience. 2024 Sep 3; 27(9): 110880.
[2]. Herkenne S, Ek O, Zamberlan M, Pellattiero A, et al. Developmental and Tumor Angiogenesis Requires the Mitochondria-Shaping Protein Opa1[J]. Cell Metabolism. 2020 May 5; 31(5): 987-1003.
[3]. Noguchi M, Kohno S, Pellattiero A, et al. Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinomaresistant cell line[J]. Cell Death Disease. 2023 Apr 5; 14(4): 241.
[4]. Baek ML, Lee J, Pendleton KE, et al. Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment[J]. Oncogene. 2023 Mar; 42(14): 1117-1131.
[5]. Wang Y, Wang Y, Liu W, et al. TIM-4 orchestrates mitochondrial homeostasis to promote lung cancer progression via ANXA2/PI3K/AKT/OPA1 axis[J]. Cell Death Disease. 2023 Feb 20; 14(2): 141.
[6]. Guo Y, Luo C, Sun Y, et al. Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy[J]. Biomedicine Pharmacotherapy. 2023 Oct; 166: 115342.
[7]. Zamberlan M, Boeckx A, Muller F, et al. Inhibition of the mitochondrial protein Opa1 curtails breast cancer growth[J]. Journal of Experimental & Clinical Cancer Research. 2022 Mar 12; 41(1): 95
[8]. Jiang HL, Yang HH, Liu YB, et al. L-OPA1 deficiency aggravates necroptosis of alveolar epithelial cells through impairing mitochondrial function during acute lung injury in mice[J]. Journal of Cellular Physiology. 2022 Jul; 237(7): 3030-3043.
MYLS22是视神经萎缩1（OPA1）的选择性抑制剂。MYLS22通过靶向内皮OPA1来抑制肿瘤生长，并通过影响NF-kB活性和血管生成基因表达来抑制血管生成。它具有抗血管生成和抗癌活性 [1-7]。
MYLS22（50μM）在2天后抑制PANC-1细胞的生长，并在72小时后减少细胞迁移 [1]。MYLS22（30μM，72h）可恢复吉非替尼诱导的PC9M2细胞线粒体凋亡 [3]。MYLS22（50μM，48h）显着增加阿霉素诱导的细胞杀伤力，并降低阿霉素介导的线粒体伸长和OXPHOS [4]。MYLS22（50μM，24h）通过抑制OPA1逆转TIM-4诱导的OXPHOS增强并破坏线粒体融合，从而减弱肺癌进展 [5]。
在使用C57BL6/J小鼠的皮下B16F10小鼠黑色素瘤模型中，MYLS22（10mg/kg，ip，6d）有效抑制了黑色素瘤的增殖和生长 [2]。在使用KSN/Slc小鼠的皮下PC9M2异种移植模型中，MYLS22（25mg/kg，po，18d）逆转了肺腺癌细胞对吉非替尼的体内耐药性，抑制了肿瘤增殖并诱导了肿瘤细胞死亡 [3]。在雌性无胸腺裸鼠的A549异种移植瘤模型中，MYLS22（10mg/kg，ip，18d）显著增强了BAY-876的抗癌效果 [6]。在雌性小鼠的MDA-MB-231异种移植瘤模型中，MYLS22（10mg/kg，ip，18d）通过抑制肿瘤生长、侵袭性和新生血管形成抑制了TNBC小鼠的生长 [7]。MYLS22（0、12.5、25和50mg/kg）抑制了L-OPA1，导致小鼠肺组织损伤更严重，并上调了体内炎症细胞因子总IL-1β、IL-1β p17和NF-κB p65。其中，12.5mg/kg MYLS22足以引起小鼠严重的肺损伤和炎症 [8]。