Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated downstream of p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. CC-99677 is a novel, irreversible, covalent MK2 inhibitor under development for the treatment of ankylosing spondylitis (AS) and other inflammatory diseases. As part of a phase I clinical trial to assess safety and tolerability, we evaluated target engagement, pharmacokinetics, and pharmacodynamics of CC-99677. The MK2 inhibitor CC-99677 was evaluated for its effect on cytokine expression in vitro in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with a definitive AS diagnosis. A novel in vitro model was developed to compare the potential for tachyphylaxis of CC-99677 and p38 inhibitors in THP-1 cells. The effect of CC-99677 on tristetraprolin (TTP) and cytokine mRNA was assessed in stimulated human monocyte-derived macrophages. In a first-in-human study, thirty-seven healthy volunteers were randomly assigned to daily oral doses of CC-99677 or placebo, and blood was collected at pre-specified time points before and after dosing. CC-99677 concentrations were assessed in the plasma, and CC-99677 binding to MK2 was evaluated in PBMCs. Ex vivo stimulation of the whole blood was conducted from participants in the first-in-human study to assess the pharmacodynamic effects. In vitro, CC-99677 inhibited tumor necrosis factor (TNF), interleukin (IL)-6, and IL-17 protein production in samples of monocytes and macrophages from AS patients and healthy volunteers via an mRNA-destabilization mechanism. In the in vitro model of tachyphylaxis, CC-99677 showed a differentiated pattern of sustained TNF protein inhibition compared with p38 inhibitors. CC-99677 reduced TTP phosphorylation and accelerated the decay of inflammatory cytokine mRNA in lipopolysaccharide-stimulated macrophages. Administration of CC-99677 to healthy volunteers was safe and well-tolerated, with linear pharmacokinetics and sustained reduction of ex vivo whole blood TNF, IL-6, and chemokine synthesis. CC-99677 inhibition of MK2 is a promising approach for the treatment of inflammatory diseases and may overcome the limitations of p38 MAPK inhibition. ClinicalTrials.gov NCT03554993 .

中文翻译：

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CC-99677 是一种新型口服选择性共价 MK2 抑制剂，可持续减少促炎细胞因子的产生


丝裂原激活蛋白激酶 (MAPK) 激活蛋白激酶 2 (MK2) 在 p38 MAPK 下游被激活，并调节编码炎症细胞因子的 mRNA 的稳定性。 CC-99677 是一种新型、不可逆、共价 MK2 抑制剂，正在开发用于治疗强直性脊柱炎 (AS) 和其他炎症性疾病。作为评估安全性和耐受性的 I 期临床试验的一部分，我们评估了 CC-99677 的靶点参与、药代动力学和药效学。体外评估了 MK2 抑制剂 CC-99677 对来自健康捐献者和明确 AS 诊断患者的外周血单核细胞 (PBMC) 中细胞因子表达的影响。开发了一种新型体外模型来比较 CC-99677 和 p38 抑制剂在 THP-1 细胞中快速耐受的潜力。在受刺激的人单核细胞来源的巨噬细胞中评估了 CC-99677 对三四脯氨酸 (TTP) 和细胞因子 mRNA 的影响。在一项首次人体研究中，37 名健康志愿者被随机分配每日口服 CC-99677 或安慰剂，并在给药前后预先指定的时间点采集血液。评估血浆中的 CC-99677 浓度，并评估 PBMC 中的 CC-99677 与 MK2 的结合。首次人体研究的参与者对全血进行了体外刺激，以评估药效学效果。在体外，CC-99677 通过 mRNA 不稳定机制抑制 AS 患者和健康志愿者的单核细胞和巨噬细胞样本中肿瘤坏死因子 (TNF)、白细胞介素 (IL)-6 和 IL-17 蛋白的产生。在快速耐受的体外模型中，CC-99677 与 p38 抑制剂相比显示出持续 TNF 蛋白抑制的差异模式。 CC-99677 降低了脂多糖刺激的巨噬细胞中 TTP 磷酸化并加速炎症细胞因子 mRNA 的衰减。健康志愿者给予 CC-99677 是安全且耐受性良好的，具有线性药代动力学，并且持续减少离体全血 TNF、IL-6 和趋化因子合成。 CC-99677 抑制 MK2 是治疗炎症性疾病的一种有前途的方法，并且可能克服 p38 MAPK 抑制的局限性。 ClinicalTrials.gov NCT03554993。