Apratastat

Apratastat is an orally active, reversible dual inhibitor. Apratastat suppresses the activity of tumor necrosis factor-α converting enzyme (TACE; IC₅₀=81.7ng/mL) and matrix metalloproteinases (MMPs)^[1-2]. Apratastat has potential as a therapeutic agent for cancer and rheumatoid arthritis^[3-4].

In vitro, treatment of SUM149 breast cancer cells with Apratastat (20μM) for 3 days inhibited cell growth^[5]. Pretreatment of non-small cell lung cancer NCI-H358 cells with Apratastat (25μM) for 24–48 hours suppressed radiation-induced tumor cell migration via inhibiting MAPK pathway-mediated EphA2 S897 phosphorylation^[6].

In vivo, in a COVID-19-associated lung injury model using C57BL/6 mice, Apratastat (10mg/kg) was administered via intraperitoneal injection (at 4 and 16 hours) or intranasally (at 24 hours). Apratastat significantly improved lung histopathology scores and alleviated features of acute lung injury, such as edema, fibrosis, and vascular congestion^[7]. In OVE26 diabetic model mice, Apratastat (10mg/kg; twice daily) was administered via intraperitoneal injection for three consecutive weeks. Apratastat significantly inhibited ADAM17 activity in the renal cortex, reduced Nox4 expression and NADPH oxidase activity, thereby mitigating the progression of diabetes-related kidney injury^[8].

References:
[1] Talele TT, Khedkar SA, Rigby AC. Successful applications of computer aided drug discovery: moving drugs from concept to the clinic. Curr Top Med Chem. 2010;10(1):127-41.
[2] Shu C, Zhou H, Afsharvand M, et al. Pharmacokinetic-pharmacodynamic modeling of apratastat: a population-based approach. J Clin Pharmacol. 2011 Apr;51(4):472-81.
[3] Moss ML, Sklair-Tavron L, Nudelman R. Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol. 2008 Jun;4(6):300-9.
[4] Sharma A, Bender S, Zimmermann M, et al. Secretome Signature Identifies ADAM17 as Novel Target for Radiosensitization of Non-Small Cell Lung Cancer. Clin Cancer Res. 2016 Sep 1;22(17):4428-39.
[5] Mezil L, Berruyer-Pouyet C, Cabaud O, et al. Tumor selective cytotoxic action of a thiomorpholin hydroxamate inhibitor (TMI-1) in breast cancer. PLoS One. 2012;7(9):e43409.
[6] Waller V, Tschanz F, Winkler R, et al. The role of EphA2 in ADAM17- and ionizing radiation-enhanced lung cancer cell migration. Front Oncol. 2023 Mar 14;13:1117326.
[7] Lartey NL, Valle-Reyes S, Vargas-Robles H, et al. ADAM17/MMP inhibition prevents neutrophilia and lung injury in a mouse model of COVID-19. J Leukoc Biol. 2022 Jun;111(6):1147-1158.
[8] Ford BM, Eid AA, Göőz M, et al. ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice. Am J Physiol Renal Physiol. 2013 Aug 1;305(3):F323-32.

Apratastat是一种口服活性、可逆的双重抑制剂，能够抑制肿瘤坏死因子-α转换酶（TACE；IC₅₀=81.7ng/mL）和基质金属蛋白酶（MMPs）的活性^[1-2]。Apratastat有潜力成为治疗癌症，及类风湿关节炎药物的潜力^[3-4]。

在体外，Apratastat（20μM）处理SUM149乳腺癌细胞3天，对细胞的生长有抑制效果^[5]。Apratastat（25μM）预处理非小细胞肺癌NCI-H358细胞24–48小时，Apratastat通过旁分泌机制抑制MAPK通路介导的EphA2 S897磷酸化，从而抑制辐射诱导的肿瘤细胞迁移^[6]。

在体内，Apratastat（10mg/kg）通过腹腔注射（4h和16h后各一次）或鼻内给药（24h后）处理COVID-19相关肺损伤的C57BL/6小鼠，Apratastat显著改善肺组织病理学评分，减轻水肿、纤维化和血管充血等急性肺损伤特征^[7]。Apratastat（10mg/kg；每日两次）通过腹腔注射处理OVE26糖尿病模型小鼠连续3周，Apratastat显著抑制了肾皮质中ADAM17的活性，并降低了Nox4的表达和NADPH氧化酶的活性，从而缓解了糖尿病相关的肾损伤进程^[8]。