UlixertinibBVD-523AbMoleM5345是一种高选择性、可逆的细胞外信号调节激酶ERK1/2抑制剂在多种细胞和动物模型中展现出显著的靶向抑制活性。在神经母细胞瘤NB研究中Ulixertinib在低纳摩尔浓度范围内即可有效抑制MAPK通路的活性并显著降低SK-N-BE(2、IMR-32等NB细胞系的细胞增殖与集落形成能力同时还能诱导细胞周期阻滞并促进凋亡、增强NB细胞对阿霉素Doxorubicin的敏感性[1]。在胶质瘤模型中针对携带KIAA1549:BRAF融合或BRAFV600E突变的BT40和DKFZ-BT66细胞系UlixertinibVRT752271在体外以低纳摩尔浓度抑制细胞活力并在斑马鱼胚胎和小鼠体内模型中证实其靶点抑制效应及抗肿瘤作用[2]。在横纹肌肉瘤RMS研究中Ulixertinib CAS No.869886-67-9与MCL-1抑制剂S63845联用可在体外快速诱导Caspase活化及凋亡并在小鼠模型中显著抑制RMS细胞的长期存活机制上涉及BIM和BMF的上调[3]。在胰腺导管腺癌PDAC细胞系如MIA PaCa-2和PANC-1中UlixertinibCAS No.869886-67-9单一处理能有效抑制生长并在与吉西他滨Gemcitabine联用时表现出协同细胞毒性[4]。在肺癌研究中UlixertinibBVD-523可有效逆转RAD21驱动的转移尤其在KRAS突变背景下在小鼠模型中显著抑制肺腺癌LUAD进展[5]此外在脑转移模型中Ulixertinib能穿透血脑屏障并在小鼠中减少脑转移发生率、延长生存期[6]。药代动力学研究表明UlixertinibGemzar在小鼠、大鼠和犬中口服给药后吸收迅速半衰期介于1.0–2.5 h[7]。综合来看UlixertinibBVD-523AbMoleM5345凭借其明确的靶向机制、良好的体内暴露特性及广泛的协同潜力已成为解析MAPK通路功能及开发联合干预策略的重要科研工具。参考文献及鸣谢[1] Yu, Y.; Zhao, Y.; Choi, J. et al. ERK Inhibitor Ulixertinib Inhibits High-Risk Neuroblastoma Growth In Vitro and In Vivo. Cancers2022, 14 (22).[2] Sigaud, R. Rosch, L. Gatzweiler, C. et al. The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models. Neuro-oncology2023, 25 (3), 566-579.[3] Winkler, M. Friedrich, J. Boedicker, C. et al. Co-targeting MCL-1 and ERK1/2 kinase induces mitochondrial apoptosis in rhabdomyosarcoma cells. Translational oncology2022, 16, 101313.[4] Jiang, H. Xu, M. Li, L. et al. Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models. Molecular cancer therapeutics2018, 17 (10), 2144-2155.[5] Xiao, C. Fan, T. Wang, D. et al. RAD21-mediated epigenetic regulation promotes lung adenocarcinoma progression and sensitizes cancer cells to ERK-targeted therapy. Cancer letters2025, 634, 218062.[6] Tiong, T. Y.; Chan, M. L. Wang, C. H. et al. Exosomal miR-21 determines lung-to-brain metastasis specificity through the DGKB/ERK axis within the tumor microenvironment. Life sciences2023, 329, 121945.[7] Suresh, P. S. Jairam, R. K. Chandrasekhar, D. V. et al. Prediction of Human Pharmacokinetics of Ulixertinib, a Novel ERK1/2 Inhibitor from Mice, Rats, and Dogs Pharmacokinetics. European journal of drug metabolism and pharmacokinetics2018, 43 (4), 453-460.细胞系A375 cells方法Cells were serum-starved overnight, and treated with BVD-523 (2 µM) or PD184352 (10 µM) for 30 min. before to PMA stimulation (100 ng/ml) for another 30 min. Cells were lysed in RIPA buffer and CDK12 immunoprecipitates were washed thrice in lysis buffer followed by three washes in kinase buffer.浓度2 µM处理时间30 min参考文献Nat Commun. 2022 Oct 29;13(1):6457.* 上述方法来自公开文献仅供相同目的实验参考。如实验目的、材料、方法不同请参考其他文献。动物实验参考动物模型Nude mice配制BVD-523 was suspended in 1% (w/v) CMC at the desired concentration and homogenized on ice at 6,500 rpm for 50 minutes.剂量50-100 mg/kg给药处理Oral gavage参考文献Mol Cancer Ther. 2017 Nov;16(11):2351-2363.*上述方法来自公开文献仅供相同目的实验参考。如实验目的、材料、方法不同请参考其他文献。体内实验的工作液建议现用现配当天使用如在配制过程中出现沉淀、析出现象可以通过超声和或加热的方式助溶。切勿一次性将产品全部溶解。建议制定动物给药及实验方案时尽量参考已发表的相关实验文献溶剂种类及配比众多简单地溶解目的化合物并不能解决动物给药依从性、体内生物利用度、组织分布等相关问题未必能保证目的化合物在动物体内充分发挥生物学效用。
AbMole丨Ulixertinib：靶向ERK1/2通路的抑制剂的科研应用
UlixertinibBVD-523AbMoleM5345是一种高选择性、可逆的细胞外信号调节激酶ERK1/2抑制剂在多种细胞和动物模型中展现出显著的靶向抑制活性。在神经母细胞瘤NB研究中Ulixertinib在低纳摩尔浓度范围内即可有效抑制MAPK通路的活性并显著降低SK-N-BE(2、IMR-32等NB细胞系的细胞增殖与集落形成能力同时还能诱导细胞周期阻滞并促进凋亡、增强NB细胞对阿霉素Doxorubicin的敏感性[1]。在胶质瘤模型中针对携带KIAA1549:BRAF融合或BRAFV600E突变的BT40和DKFZ-BT66细胞系UlixertinibVRT752271在体外以低纳摩尔浓度抑制细胞活力并在斑马鱼胚胎和小鼠体内模型中证实其靶点抑制效应及抗肿瘤作用[2]。在横纹肌肉瘤RMS研究中Ulixertinib CAS No.869886-67-9与MCL-1抑制剂S63845联用可在体外快速诱导Caspase活化及凋亡并在小鼠模型中显著抑制RMS细胞的长期存活机制上涉及BIM和BMF的上调[3]。在胰腺导管腺癌PDAC细胞系如MIA PaCa-2和PANC-1中UlixertinibCAS No.869886-67-9单一处理能有效抑制生长并在与吉西他滨Gemcitabine联用时表现出协同细胞毒性[4]。在肺癌研究中UlixertinibBVD-523可有效逆转RAD21驱动的转移尤其在KRAS突变背景下在小鼠模型中显著抑制肺腺癌LUAD进展[5]此外在脑转移模型中Ulixertinib能穿透血脑屏障并在小鼠中减少脑转移发生率、延长生存期[6]。药代动力学研究表明UlixertinibGemzar在小鼠、大鼠和犬中口服给药后吸收迅速半衰期介于1.0–2.5 h[7]。综合来看UlixertinibBVD-523AbMoleM5345凭借其明确的靶向机制、良好的体内暴露特性及广泛的协同潜力已成为解析MAPK通路功能及开发联合干预策略的重要科研工具。参考文献及鸣谢[1] Yu, Y.; Zhao, Y.; Choi, J. et al. ERK Inhibitor Ulixertinib Inhibits High-Risk Neuroblastoma Growth In Vitro and In Vivo. Cancers2022, 14 (22).[2] Sigaud, R. Rosch, L. Gatzweiler, C. et al. The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models. Neuro-oncology2023, 25 (3), 566-579.[3] Winkler, M. Friedrich, J. Boedicker, C. et al. Co-targeting MCL-1 and ERK1/2 kinase induces mitochondrial apoptosis in rhabdomyosarcoma cells. Translational oncology2022, 16, 101313.[4] Jiang, H. Xu, M. Li, L. et al. Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models. Molecular cancer therapeutics2018, 17 (10), 2144-2155.[5] Xiao, C. Fan, T. Wang, D. et al. RAD21-mediated epigenetic regulation promotes lung adenocarcinoma progression and sensitizes cancer cells to ERK-targeted therapy. Cancer letters2025, 634, 218062.[6] Tiong, T. Y.; Chan, M. L. Wang, C. H. et al. Exosomal miR-21 determines lung-to-brain metastasis specificity through the DGKB/ERK axis within the tumor microenvironment. Life sciences2023, 329, 121945.[7] Suresh, P. S. Jairam, R. K. Chandrasekhar, D. V. et al. Prediction of Human Pharmacokinetics of Ulixertinib, a Novel ERK1/2 Inhibitor from Mice, Rats, and Dogs Pharmacokinetics. European journal of drug metabolism and pharmacokinetics2018, 43 (4), 453-460.细胞系A375 cells方法Cells were serum-starved overnight, and treated with BVD-523 (2 µM) or PD184352 (10 µM) for 30 min. before to PMA stimulation (100 ng/ml) for another 30 min. Cells were lysed in RIPA buffer and CDK12 immunoprecipitates were washed thrice in lysis buffer followed by three washes in kinase buffer.浓度2 µM处理时间30 min参考文献Nat Commun. 2022 Oct 29;13(1):6457.* 上述方法来自公开文献仅供相同目的实验参考。如实验目的、材料、方法不同请参考其他文献。动物实验参考动物模型Nude mice配制BVD-523 was suspended in 1% (w/v) CMC at the desired concentration and homogenized on ice at 6,500 rpm for 50 minutes.剂量50-100 mg/kg给药处理Oral gavage参考文献Mol Cancer Ther. 2017 Nov;16(11):2351-2363.*上述方法来自公开文献仅供相同目的实验参考。如实验目的、材料、方法不同请参考其他文献。体内实验的工作液建议现用现配当天使用如在配制过程中出现沉淀、析出现象可以通过超声和或加热的方式助溶。切勿一次性将产品全部溶解。建议制定动物给药及实验方案时尽量参考已发表的相关实验文献溶剂种类及配比众多简单地溶解目的化合物并不能解决动物给药依从性、体内生物利用度、组织分布等相关问题未必能保证目的化合物在动物体内充分发挥生物学效用。
