Bristol Myers Squibb, Princeton, New Jersey.
Bristol Myers Squibb, Princeton, New Jersey.
Transl Res. 2022 Nov;249:49-73. doi: 10.1016/j.trsl.2022.06.005. Epub 2022 Jun 9.
As an anti-inflammatory strategy, MAPK-activated protein kinase-2 (MK2) inhibition can potentially avoid the clinical failures seen for direct p38 inhibitors, especially tachyphylaxis. CC-99677, a selective targeted covalent MK2 inhibitor, employs a rare chloropyrimidine that bonds to the sulfur of cysteine 140 in the ATP binding site via a nucleophilic aromatic substitutions (SAr) mechanism. This irreversible mechanism translates biochemical potency to cells shown by potent inhibition of heat shock protein 27 (HSP27) phosphorylation in LPS-activated monocytic THP-1 cells. The cytokine inhibitory profile of CC-99677 differentiates it from known p38 inhibitors, potentially suppressing a p38 pathway inflammatory response while avoiding tachyphylaxis. Dosed orally, CC-99677 is efficacious in a rat model of ankylosing spondylitis. Single doses, 3 to 400 mg, in healthy human volunteers show linear pharmacokinetics and apparent sustained tumor necrosis factor-α inhibition, with a favorable safety profile. These results support further development of CC-99677 for autoimmune diseases like ankylosing spondylitis.
作为一种抗炎策略，MAPK 激活的蛋白激酶-2（MK2）抑制可能避免直接 p38 抑制剂的临床失败，特别是快速耐受性。CC-99677 是一种选择性靶向共价 MK2 抑制剂，采用罕见的氯嘧啶，通过亲核芳香取代（SAr）机制与 ATP 结合位点的半胱氨酸 140 的硫键合。这种不可逆的机制将生物化学效力转化为细胞，在脂多糖激活的单核细胞 THP-1 细胞中强烈抑制热休克蛋白 27（HSP27）磷酸化。CC-99677 的细胞因子抑制谱使其与已知的 p38 抑制剂区分开来，可能抑制 p38 通路炎症反应，同时避免快速耐受性。在强直性脊柱炎的大鼠模型中，CC-99677 口服有效。在健康志愿者中，单次剂量为 3 至 400mg，呈线性药代动力学和明显的持续肿瘤坏死因子-α抑制作用，具有良好的安全性。这些结果支持进一步开发 CC-99677 用于治疗强直性脊柱炎等自身免疫性疾病。
