CBL0137

CBL0137 is a first-in-class small molecule compound that targets the FACT complex to modulate chromatin structure and gene expression. It can inhibit the activity of the NF-κB signaling pathway and has anti-cancer and anti-inflammatory properties^[1]. As a selective inhibitor of the NF-κB transcription factor, which plays a key role in regulating inflammation, cell survival, and proliferation, CBL0137 can effectively reduce the expression of pro-inflammatory cytokines and chemokines, thereby alleviating inflammatory responses in various disease models^[2-3]. CBL0137 has demonstrated significant anti-tumor activity in preclinical studies. Its unique mechanism of action and broad-spectrum activity make CBL0137 a promising candidate for further clinical development in oncology and inflammatory diseases^[4].

In vitro, CBL0137 (0.25–4μM) was used to treat ovarian cancer cell lines (A2780, A2780CP, ID8, OVCAR3, and SKOV3). CBL0137 inhibits the function of the chromatin remodeling complex FACT, leading to decreased transcription of antioxidant genes and increased intracellular reactive oxygen species (ROS) levels. The elevated ROS levels induce the aggregation of BAX protein on the mitochondrial membrane, leading to the release of cytochrome c (Cyt c), activation of caspase-3, and subsequent cleavage of GSDME. This forms pores in the cell membrane, causing cell swelling, rupture, and release of lactate dehydrogenase (LDH), ultimately inducing pyroptosis^[5]. CBL0137 (250nM) in combination with Rovalpituzumab tesirine (Rova-T) was used to treat tumor-initiating cells (TICs) in small cell lung cancer (SCLC). The combination significantly reduced the viability of TICs and decreased SOX2 protein levels, indicating enhanced targeting of TICs^[6].

In vivo, CBL0137 (60mg/kg) in combination with cisplatin (5mg/kg) was administered to mice bearing small cell lung cancer (SCLC) tumors via intravenous and intraperitoneal injection, respectively, once a week. The combination of CBL0137 and cisplatin significantly inhibited SCLC tumor growth and extended the survival of mice without noticeable toxicity^[7]. In another study, CBL0137 (70mg/kg) was administered intravenously to nude mice bearing glioblastoma (GBM) tumors, once a week for four doses. Mice received 2.5Gy of radiotherapy 24 hours after CBL0137 treatment. The combination of CBL0137 and radiotherapy significantly prolonged the survival of mice. Additionally, the combination treatment significantly reduced the frequency of cancer stem cells (CSCs) in tumors and decreased the number of Sox2-positive cells^[8].

References:
[1] Jin MZ, Xia BR, Xu Y, et al. Curaxin CBL0137 Exerts Anticancer Activity via Diverse Mechanisms. Front Oncol. 2018 Dec 7;8:598.
[2] Singh A, Pruett N, Dixit S, et al. Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy. J Exp Clin Cancer Res. 2023 Nov 16;42(1):304.
[3] Yu L, Yang Y, Wang J, et al. PDCD4 promotes inflammation/fibrosis by activating the PPAR‑γ/NF‑κB pathway in mouse atrial myocytes. Mol Med Rep. 2024 Nov;30(5):209.
[4] Forgione MO, McClure BJ, Page EC, et al. TP53 loss‑of‑function mutations reduce sensitivity of acute leukaemia to the curaxin CBL0137. Oncol Rep. 2022 May;47(5):99.
[5] Yang C, Wang ZQ, Zhang ZC, et al. CBL0137 activates ROS/BAX signaling to promote caspase-3/GSDME-dependent pyroptosis in ovarian cancer cells. Biomed Pharmacother. 2023 May;161:114529.
[6] Lindner DJ, Wildey G, Parker Y, et al. CBL0137 increases the targeting efficacy of Rovalpituzumab tesirine against tumour-initiating cells in small cell lung cancer. Br J Cancer. 2021 Mar;124(5):893-895.
[7] De S, Lindner DJ, Coleman CJ, et al. The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1 Expression and Targeting Tumor-Initiating Cells. Cancer Res. 2018 May 1;78(9):2396-2406.
[8] Tallman MM, Zalenski AA, Deighen AM, et al. The small molecule drug CBL0137 increases the level of DNA damage and the efficacy of radiotherapy for glioblastoma. Cancer Lett. 2021 Feb 28;499:232-242.

CBL0137是一种靶向FACT复合体以调节染色质结构和基因表达的first-in-class小分子化合物，可靶向抑制NF-κB信号通路活性，具有抗癌和抗炎特性^[1]。作为在调节炎症、细胞存活和增殖中起关键作用的NF-κB转录因子的选择性抑制剂，CBL0137 能有效降低促炎细胞因子和趋化因子的表达，从而缓解各种疾病模型中的炎症反应^[2-3]，CBL0137在临床前研究中显示出抗肿瘤作用，CBL0137独特的作用机制和广谱活性使其成为肿瘤学和炎症性疾病进一步临床开发的有前途的候选药物^[4]。

在体外，CBL0137（0.25-4μM）处理卵巢癌细胞系（A2780、A2780CP、ID8、OVCAR3和SKOV3），CBL0137通过抑制染色质重塑复合体FACT的功能，降低抗氧化基因的转录，导致细胞内活性氧（ROS）水平升高。ROS的增加促使BAX蛋白在细胞线粒体膜上聚集，诱导细胞色素c（Cyt c）的释放，激活caspase-3，进而切割GSDME，形成细胞膜上的孔隙，导致细胞肿胀、破裂并释放乳酸脱氢酶（LDH），最终诱导细胞焦亡^[5]。CBL0137（250nM）与Rovalpituzumab tesirine（Rova-T）联合处理小细胞肺癌（SCLC）中的肿瘤起始细胞（TICs），CBL0137显著降低了TICs的细胞存活率，还降低了SOX2蛋白水平，表明其对TICs的靶向能力增强^[6]。

在体内，在体内，CBL0137（60mg/kg）与顺铂（5mg/kg）联合使用，通过静脉注射和腹腔注射分别给药，每周一次，治疗小细胞肺癌（SCLC）小鼠模型。CBL0137联合顺铂能够显著抑制SCLC肿瘤的生长，延长小鼠的生存期，且未观察到明显的毒性反应^[7]。CBL0137（70mg/kg）通过静脉注射治疗携带胶质母细胞瘤（GBM）的裸鼠模型，每周一次，共4次。小鼠在CBL0137给药后24小时接受2.5Gy的放射治疗。CBL0137联合放射治疗显著延长了小鼠的生存期，此外，联合治疗还显著降低了肿瘤中癌症干细胞（CSC）的频率，减少了Sox2阳性细胞的数量^[8]。