SCH772984 is a novel, potent, ATP-competitive inhibitor of ERK1 and ERK2 with IC50 values of 4nM and 1nM, respectively[1]. SCH772984 inhibits phosphorylation of the ERK substrate p90 ribosomal S6 kinase (T359/S363 phospho-RSK) and also inhibits phosphorylation of residues in the activation loop of ERK itself[2]. SCH772984 has antitumor activity against BRAF or RAS mutations in cells that are resistant to native MAPK inhibition and those that are resistant to MAPK inhibition[3].
In vitro, 11 of 14 NRAS mutant melanoma cell lines treated with SCH772984 (0-10μM) for 72-120h were highly sensitive to SCH772984 with IC50<1μM[4]. SCH772984 (0-10μM) treated human non-small cell lung cancer cell line (NCI-H727 cells) for 6h and 24h downregulated the phosphorylation of ERK and other proteins in parental H727 cells and two MEK- and ERK-resistant sublines after 6h and 24h of treatment[5].
In vivo, SCH772984 (10mg/kg) treated with intraperitoneal injection in septic mice increased the survival rate of mice, reduced the plasma levels of Ccl2/Mcp1, inhibited molecular processes related to immune response and hemostasis in the kidney and liver, and activated the extracellular matrix (ECM) organization and retinoic acid (RA) signaling pathways in the lung and liver[6]. SCH772984 (0.1, 1.0, 10μg) was injected intrathecally to treat rats with tibial bone cancer pain model, producing analgesic effects in a dose-dependent manner and significantly reducing the expression of Fos protein in the dorsal horn of the spinal cord[7].
References:
[1] Morris E J, Jha S, Restaino C R, et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors[J]. Cancer discovery, 2013, 3(7): 742-750.
[2] Li H, Wang C, Gong Z, et al. Transient Receptor Potential Ankyrin 1-dependent Activation of Extracellular Signal-regulated Kinase 2 in the Cerebral Cortices Contributes to Cortical Spreading Depolarization[J]. Neuroscience, 2024, 543: 90-100.
[3] Miao L, Tian H. Development of ERK1/2 inhibitors as a therapeutic strategy for tumour with MAPK upstream target mutations[J]. Journal of drug targeting, 2020, 28(2): 154-165.
[4] Wong D J L, Robert L, Atefi M S, et al. Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma[J]. Molecular cancer, 2014, 13: 1-15.
[5] Moschos S J, Sullivan R J, Hwu W J, et al. Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors[J]. JCI insight, 2018, 3(4).
[6] Kopczynski M, Rumienczyk I, Kulecka M, et al. Selective extracellular signal-regulated kinase 1/2 (erk1/2) inhibition by the sch772984 compound attenuates in vitro and in vivo inflammatory responses and prolongs survival in murine sepsis models[J]. International Journal of Molecular Sciences, 2021, 22(19): 10204.
[7] Bian J, Zhu S, Ma W, et al. Analgesic effect and possible mechanism of SCH772984 intrathecal injection on rats with bone cancer pain[J]. Saudi Pharmaceutical Journal, 2016, 24(3): 354-362.
SCH772984是一种新型的、有效的、ATP竞争性的ERK1和ERK2抑制剂，IC50值分别为4nM和1nM[1]。SCH772984抑制ERK底物p90核糖体S6激酶 （T359/S363磷酸-RSK）的磷酸化，还抑制ERK自身活化环中残基的磷酸化[2]。SCH772984在对天然MAPK抑制和耐药MAPK抑制的细胞中的BRAF或RAS突变，具有抗肿瘤活性[3]。
在体外，SCH772984（0-10μM）处理14个NRAS突变型黑色素瘤细胞系72-120h，其中有11个对SCH772984高度敏感，IC50<1μM[4]。SCH772984（0-10μM）处理人非小细胞肺癌细胞系（NCI-H727细胞）6h和24h，下调了亲本H727细胞以及处理6h和24h后两个MEK和ERK抗性亚系中ERK和其他蛋白质的磷酸化[5]。
在体内，SCH772984（10mg/kg）通过腹腔注射治疗脓毒症小鼠，提高了小鼠的存活率，降低了Ccl2/Mcp1的血浆水平，抑制了与肾脏和肝脏中的免疫反应和止血相关的分子过程，并激活肺和肝脏中的细胞外基质（ECM）组织和视黄酸（RA）信号通路[6]。SCH772984（0.1, 1.0,10μg）通过鞘内注射治疗胫骨骨癌疼痛模型大鼠，剂量依赖性地产生镇痛作用，显著降低了脊髓背角Fos蛋白的表达[7]。