Metroplex Clinical Research Center, Dallas, Texas, USA.
Curr Opin Rheumatol. 2010 May;22(3):330-5. doi: 10.1097/BOR.0b013e3283378e6f.
Due to the cost and parenteral mode of administration of biologics, efforts to develop oral small molecule inhibitors to protein kinases involved in cellular signaling that impact inflammatory cytokine production have been ongoing. This article will review the recent publications on these efforts.
On preclinical work, p38 mitogen-activated kinases were considered attractive targets to suppress cytokine production. Three different molecules (SCIO_469, Pamapimod, VX-702) that target the p38alpha isoform have been evaluated in phase 2 trials. Unfortunately, clinical efficacy was not observed, and dose-related toxicity was seen. The future of this approach is unclear. Targeting more upstream protein tyrosine kinases such as spleen tyrosine kinase (SyK) and the JAK family of kinases has been associated with greater success in clinical trials, with efficacy demonstrated. Adverse events occurred in a dose-dependent fashion with the SyK inhibitor, such as diarrhea and hypertension. Neutropenia, elevated liver-function tests, serum creatinine elevations and lipid elevations have occurred with JAK-kinase inhibition. Dose modifications have been made based on the phase 2 trial results; phase 3 clinical trials are ongoing.
Inhibiting downstream proteins involved in cellular signaling, such as p38, has not been successful to date. Inhibitors of more upstream protein-tyrosine kinases involved in cellular signaling appear to be viable molecular candidates for rheumatoid arthritis. If the results seen in phase 2 studies are confirmed in larger phase 3 studies, we may soon have new, oral DMARD therapies available.
由于生物制剂的成本和给药途径为注射，因此一直在努力开发可口服的小分子蛋白激酶抑制剂，以抑制影响细胞因子产生的细胞信号转导。本文将对这些研究进展进行综述。
在临床前研究中，丝裂原活化蛋白激酶 p38 被认为是抑制细胞因子产生的有吸引力的靶点。已有三种不同的靶向 p38alpha 同工型的分子（SCIO_469、Pamapimod、VX-702）在 2 期临床试验中进行了评估。遗憾的是，未观察到临床疗效，且出现了与剂量相关的毒性。该方法的未来前景尚不清楚。靶向更为上游的蛋白酪氨酸激酶，如脾酪氨酸激酶（SyK）和 JAK 激酶家族，与临床试验中的更大成功相关，已证明其疗效。SyK 抑制剂会出现剂量依赖性不良反应，如腹泻和高血压。JAK 激酶抑制会导致中性粒细胞减少、肝酶升高、血肌酐升高和血脂升高。基于 2 期临床试验结果进行了剂量调整；3 期临床试验正在进行中。
迄今为止，抑制细胞信号转导中涉及的下游蛋白（如 p38）的方法尚未成功。抑制细胞信号转导中更为上游的蛋白酪氨酸激酶的抑制剂似乎是类风湿关节炎有前途的候选药物。如果 2 期研究中的结果在更大规模的 3 期研究中得到证实，我们可能很快就会有新的、可口服的 DMARD 治疗方法。
