PD0325901

PD0325901 is an orally active, selective and non-ATP-competitive mitogen-activated protein kinase kinase (MEK) inhibitor with an IC₅₀ value of 0.33 nM^[1]. The K_i value of PD0325901 for activated MEK1 and MEK2 is 1 nM^[2]. PD0325901 inhibits the phosphorylation of ERK1/2 and induces cell apoptosis, maintaining stem cell renewal function and anti-cancer activity^[3].

In vitro, treatment of papillary thyroid carcinoma (PTC) cell lines (K2 and TPC-1) with PD0325901 (0.1 μM) for 96 h significantly inhibited cell growth and reduced intracellular ERK1/2 phosphorylation^[4]. Treatment of bone marrow monocytes/macrophages (BMMs) with PD0325901 (0.32, 0.64, 1.28 nM) for 24-96 h significantly inhibited osteoclast differentiation, inhibited osteoclast-specific gene expression, and inhibited NF-κB signaling pathway activation^[5].

In vivo, oral treatment of mice with non-small cell lung cancer (NSCLC) with PD0325901 (20 mg/kg) significantly enhanced the in vivo efficacy of PD-1 antibodies and increased lymphocyte infiltration and function^[6]. Treatment of mice with transgenic hepatocyte (TAMH) flank tumors with PD0325901 (20 mg/kg) significantly reduced the activity of MEK in cancer cells and decreased tumor growth rate^[7].

References:
[1] You K S, Yi Y W, Cho J, et al. Dual inhibition of AKT and MEK pathways potentiates the anti-cancer effect of gefitinib in triple-negative breast cancer cells[J]. Cancers, 2021, 13(6): 1205.
[2] Brown A P, Carlson T C G, Loi C M, et al. Pharmacodynamic and toxicokinetic evaluation of the novel MEK inhibitor, PD0325901, in the rat following oral and intravenous administration[J]. Cancer chemotherapy and pharmacology, 2007, 59: 671-679.
[3] Chen G, Guo Y, Li C, et al. Small molecules that promote self-renewal of stem cells and somatic cell reprogramming[J]. Stem Cell Reviews and Reports, 2020, 16: 511-523.
[4] Henderson Y C, Chen Y, Frederick M J, et al. MEK inhibitor PD0325901 significantly reduces the growth of papillary thyroid carcinoma cells in vitro and in vivo[J]. Molecular cancer therapeutics, 2010, 9(7): 1968-1976.
[5] Jiang T, Gong Y, Zhang W, et al. PD0325901, an ERK inhibitor, attenuates RANKL‐induced osteoclast formation and mitigates cartilage inflammation by inhibiting the NF-κB and MAPK pathways[J]. Bioorganic Chemistry, 2023, 132: 106321.
[6] Luo M, Xia Y, Wang F, et al. PD0325901, an ERK inhibitor, enhances the efficacy of PD-1 inhibitor in non-small cell lung carcinoma[J]. Acta Pharmaceutica Sinica B, 2021, 11(10): 3120-3133.
[7] Hennig M, Yip‐Schneider M T, Wentz S, et al. Targeting mitogen‐activated protein kinase kinase with the inhibitor PD0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems[J]. Hepatology, 2010, 51(4): 1218-1225.

PD0325901是一种具口服活性、选择性和非ATP竞争性的丝裂原活化蛋白激酶激酶（MEK）抑制剂，IC₅₀值为0.33nM^[1]。PD0325901对活化的MEK1和 MEK2的 K_i 值为1 nM^[2]。PD0325901抑制ERK1/2的磷酸化并诱导细胞凋亡，具有维持干细胞更新功能和抗癌活性^[3]。

在体外，PD0325901（0.1μM）处理甲状腺乳头状癌（PTC）细胞系（K2和TPC-1）96h，显著抑制了细胞生长，降低了细胞内ERK1/2磷酸化^[4]。PD0325901（0.32、0.64、1.28 nM）处理骨髓单核细胞/巨噬细胞（BMM）24-96h，显著抑制了破骨细胞分化，抑制了破骨细胞特异性基因表达，抑制了NF-κB信号通路激活^[5]。

在体内，PD0325901（20mg/kg）通过口服治疗非小细胞肺癌（NSCLC）小鼠，显著增强了PD-1抗体的体内疗效，增加了淋巴细胞的浸润和功能^[6]。PD0325901（20mg/kg）治疗患有转基因肝细胞（TAMH）侧腹肿瘤的小鼠，显著降低了癌细胞内MEK的活性，降低了肿瘤的生长率^[7]。