SCH772984

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.