GSK 3008348 hydrochloride is a small molecule antagonist targeting integrin αvβ6 (IC50=1.50nM). GSK 3008348 hydrochloride also inhibits the activity of αvβ1 (IC50=2.83nM), αvβ3 (IC50=12.53nM), αvβ5 (IC50=4.00nM), and αvβ8 (IC50=2.26nM)[1-2]. GSK 3008348 hydrochloride can be used in research related to pulmonary fibrosis and various cancers[3-4].
In vitro, PK-15 cells were treated with GSK 3008348 hydrochloride (100nM) 1 hour before viral infection. GSK 3008348 hydrochloride significantly inhibited FMDV viral RNA (vRNA) replication and virus production[5]. NHBE cells were incubated with GSK 3008348 hydrochloride (0.26nM) for 2-24 hours. At 2 hours. GSK 3008348 hydrochloride induced the internalization of αvβ6 integrin from the cell surface; at 24 hours, GSK 3008348 hydrochloride significantly reduced the total intracellular level of αvβ6 integrin[6].
In vivo, a mouse model of bleomycin-induced pulmonary fibrosis was treated with GSK 3008348 hydrochloride (prophylactic study: 15mg/kg; s.c. osmotic pump; for 14 days; therapeutic study: 3mg/kg; intranasal inhalation; twice daily for 14 days). GSK 3008348 hydrochloride inhibited the activation of TGF-β and demonstrated a prolonged duration of action[7].
References:
[1] Procopiou PA, Anderson NA, Barrett J, et al. Discovery of ( S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvβ6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis. J Med Chem. 2018 Sep 27;61(18):8417-8443.
[2] Han Z, Ma Y, Cao G, et al. Integrin αVβ1 regulates procollagen I production through a non-canonical transforming growth factor β signaling pathway in human hepatic stellate cells. Biochem J. 2021 May 14;478(9):1689-1703.
[3] Maden CH, Fairman D, Chalker M, et al. Safety, tolerability and pharmacokinetics of GSK3008348, a novel integrin αvβ6 inhibitor, in healthy participants. Eur J Clin Pharmacol. 2018 Jun;74(6):701-709.
[4] Maher TM, Simpson JK, Porter JC, et al. A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor. Respir Res. 2020 Mar 26;21(1):75.
[5] Tang J, Abdullah SW, Li P, et al. Heat Shock Protein 60 Is Involved in Viral Replication Complex Formation and Facilitates Foot and Mouth Virus Replication by Stabilizing Viral Nonstructural Proteins 3A and 2C. mBio. 2022 Oct 26;13(5):e0143422.
[6] Hryczanek HF, Barrett J, Barrett TN, et al. Core Modifications of GSK3335103 toward Orally Bioavailable αvβ6 Inhibitors with Improved Synthetic Tractability. J Med Chem. 2024 Nov 14;67(21):19689-19715.
[7] John AE, Graves RH, Pun KT, et al. Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis. Nat Commun. 2020 Sep 16;11(1):4659.
GSK 3008348 hydrochloride是一种针对整合素αvβ6（IC50=1.50nM）的小分子拮抗剂。GSK 3008348 hydrochloride还可抑制αvβ1（IC50=2.83nM）、αvβ3（IC50=12.53nM）、αvβ5（IC50=4.00nM）、αvβ8（IC50=2.26nM）的活性[1-2]。GSK 3008348 hydrochloride可用于肺纤维化和多种癌症的相关研究[3-4]。
在体外，GSK 3008348 hydrochloride（100nM）处理在病毒感染前1小时PK-15细胞。GSK 3008348 hydrochloride显著抑制FMDV的病毒RNA（vRNA）复制和病毒产生[5]。GSK 3008348 hydrochloride（0.26nM）孵育NHBE细胞2-24小时。在2小时，GSK 3008348 hydrochloride可诱导细胞表面的αvβ6整合素发生内化；24小时，GSK 3008348 hydrochloride可显著降低细胞内的总αvβ6整合素水平[6]。
在体内，GSK 3008348 hydrochloride（预防性研究：15mg/kg；s.c. osmotic pump；14天；治疗性研究：3mg/kg；吸入；一天两次；持续14天）处理博来霉素诱导肺纤维化的小鼠模型。GSK 3008348 hydrochloride抑制TGF-β的激活，并具有持久的作用时间[7]。