CWHM-12 is a potent inhibitor of αV integrins with IC50 values of 0.2, 0.8, 1.5, and 1.8nM for αvβ8, αvβ3, αvβ6, and αvβ1[1]. The αV integrin family comprises a group of heterodimeric transmembrane receptors that recognize RGD-containing extracellular matrix proteins and play key roles in mediating cell adhesion, migration, TGF-β activation, and tissue remodeling[2]. CWHM-12 is usually used in research on liver fibrosis, lung fibrosis, and tumor microenvironment[3][4].
In vitro, CWHM-12 (1mM; 3h) completely abolished odontogenesis-associated phosphoprotein (ODAPH)-mediated Tgfb1 upregulation and reversed Alpl expression in mouse ameloblast-lineage cells (ALCs)[5].
In vivo, CWHM-12 (100mg/kg/day; 4 weeks; continuous subcutaneous infusion via mini-osmotic pumps) reversed established liver fibrosis, reduced hepatic collagen content, decreased α-SMA-positive activated hepatic stellate cells, induced HSC apoptosis, and suppressed TGFβ/SMAD3 signaling in a choline deficient, amino-acid defined, high-fat diet (CDAHFD) -induced NASH mouse model[6]. CWHM-12 (100mg/kg/day; 45 days; continuous subcutaneous infusion via mini-osmotic pumps) reduced lung and spleen bacterial burden, decreased alveolar macrophages and neutrophils while increasing recruited macrophages, suppressed iNOS, MIP-2 and IL-10 production, and enhanced collagen deposition in Mycobacterium tuberculosis HN878-infected C3HeB/FeJ mice[7].
References:
[1] Henderson NC, Arnold TD, Katamura Y, et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013;19(12):1617-1624.
[2] Lafrenie RM, Yamada KM. Integrin-dependent signal transduction. J Cell Biochem. 1996;61(4):543-553.
[3] Basta J, Robbins L, Stout L, Prinsen MJ, Griggs DW, Rauchman M. Pharmacologic inhibition of RGD-binding integrins ameliorates fibrosis and improves function following kidney injury. Physiol Rep. 2020;8(7):e14329.
[4] Fausther M, Dranoff JA. Integrins, myofibroblasts, and organ fibrosis. Hepatology. 2014;60(2):756-758.
[5] Li M, Zhang J, Xiao S, et al. Odontogenesis-associated phosphoprotein (ODAPH) Promotes Ameloblast adhesion and alkaline phosphatase (ALP) expression via LAMC2/ ITGB6/TGF-β1 signaling pathway. PLoS One. 2025;20(7):e0328263.
[6] Ulmasov B, Noritake H, Carmichael P, Oshima K, Griggs DW, Neuschwander-Tetri BA. An Inhibitor of Arginine-Glycine-Aspartate-Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis. Hepatol Commun. 2018;3(2):246-261.
[7] Scott NR, Thirunavukkarasu S, Rangel-Moreno J, Griggs DW, Khader SA. CWHM-12, an Antagonist of Integrin-Mediated Transforming Growth Factor-Beta Activation Confers Protection During Early Mycobacterium tuberculosis Infection in Mice. J Interferon Cytokine Res. 2022;42(8):421-429.
CWHM-12是一种强效的αV整合素抑制剂，对αvβ8、αvβ3、αvβ6和αvβ1的IC50值分别为0.2、0.8、1.5和1.8nM[1]。αV整合素家族是一类异二聚体跨膜受体，可识别含RGD序列的细胞外基质蛋白，在介导细胞黏附、迁移、TGF-β激活和组织重塑中发挥关键作用[2]。CWHM-12通常用于肝纤维化、肺纤维化及肿瘤微环境等研究[3][4]。
在体外，CWHM-12（1mM；3h）可完全消除小鼠成釉细胞系细胞（ALCs）中牙形成相关磷酸蛋白（ODAPH）介导的Tgfb1上调，并逆转Alpl的表达[5]。
在体内，CWHM-12（100mg/kg/天；4周；微型渗透泵持续皮下输注）可逆转胆碱缺乏、氨基酸限定、高脂肪饮食（CDAHFD）诱导的NASH小鼠模型中已建立的肝纤维化，降低肝脏胶原含量，减少α-SMA阳性的活化肝星状细胞，诱导HSC凋亡，并抑制TGFβ/SMAD3信号传导[6]。CWHM-12（100mg/kg/天；45天；微型渗透泵持续皮下输注）可降低结核分枝杆菌HN878感染的C3HeB/FeJ小鼠的肺和脾脏细菌负荷，减少肺泡巨噬细胞和中性粒细胞同时增加募集型巨噬细胞，抑制iNOS、MIP-2和IL-10的产生，并增强胶原沉积[7]。