PRI-724 (C-82 prodrug, ICG-001 analog) is a first-in-class Wnt signaling modulator that inhibits the interaction between cAMP response element (CREB) binding protein and β-catenin[1]. The Wnt signaling pathway is a complex protein action network, whose functions are most commonly seen in embryonic development and cancer, but also involved in normal physiological processes in adult animals[2]. PRI-724 has anti-tumor and anti-fibrotic activities[3, 4].
In vitro, PRI-724 (25μM) treatment of human osteosarcoma cell line (SJSA-1 cells) for 24h significantly inhibited cell migration and invasion, and reduced the expression level of G1/S-specific cyclin D1 (Cyclind1)[5]. PRI-724 (0-40μM) treated head and neck squamous cell carcinoma (HNSCC) cell lines (Cal 27 and FADU cells) and significantly inhibited cell growth, with IC50 values of 8.3μM and 14.6μM for Cal 27 and FADU cells, respectively[6].
In vivo, PRI-724 (10mg/kg) was subcutaneously implanted via osmotic minipumps to treat mice with bleomycin-induced pulmonary fibrosis, which improved lung fibrosis, reduced the number of alveolar macrophages, and decreased the level of TGF-β1 in bronchoalveolar fluid (BALF)[7].
References:
[1] El-Khoueiry A B, Ning Y, Yang D, et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors[J]. 2013.
[2] Anastas J N, Moon R T. WNT signalling pathways as therapeutic targets in cancer[J]. Nature Reviews Cancer, 2013, 13(1): 11-26.
[3] Gabata R, Harada K, Mizutani Y, et al. Anti-tumor activity of the small molecule inhibitor PRI-724 against β-catenin-activated hepatocellular carcinoma[J]. Anticancer research, 2020, 40(9): 5211-5219.
[4] Osawa Y, Oboki K, Imamura J, et al. Inhibition of cyclic adenosine monophosphate (cAMP)-response element-binding protein (CREB)-binding protein (CBP)/β-catenin reduces liver fibrosis in mice[J]. EBioMedicine, 2015, 2(11): 1751-1758.
[5] Fang F, VanCleave A, Helmuth R, et al. Targeting the Wnt/β-catenin pathway in human osteosarcoma cells[J]. Oncotarget, 2018, 9(95): 36780.
[6] Kleszcz R, Frąckowiak M, Dorna D, et al. Combinations of PRI-724 Wnt/β-Catenin Pathway Inhibitor with Vismodegib, Erlotinib, or HS-173 Synergistically Inhibit Head and Neck Squamous Cancer Cells[J]. International Journal of Molecular Sciences, 2023, 24(13): 10448.
[7] Okazaki H, Sato S, Koyama K, et al. The novel inhibitor PRI-724 for Wnt/β-catenin/CBP signaling ameliorates bleomycin-induced pulmonary fibrosis in mice[J]. Experimental lung research, 2019, 45(7): 188-199.
PRI-724（C-82前药，ICG-001类似物）是首创的Wnt信号调节剂，可抑制cAMP反应元件（CREB）结合蛋白和β连环蛋白（β-catenin）相互作用[1]。Wnt信号通路是一个复杂的蛋白质作用网络，其功能最常见于胚胎发育和癌症，但也参与成年动物的正常生理过程[2]。PRI-724具有抗肿瘤、抗纤维化活性[3, 4]。
在体外，PRI-724（25μM）处理人类骨肉瘤细胞系（SJSA-1细胞）24h，显著抑制了细胞迁移和侵袭，降低了G1/S-特异性周期蛋白-D1（Cyclind1）的表达水平[5]。PRI-724（0-40μM）处理头部和颈部鳞状癌（HNSCC）细胞系（Cal 27和FADU细胞），显著抑制了细胞生长，对Cal 27和FADU细胞的IC50值分别为8.3μM和14.6μM[6]。
在体内，PRI-724（10mg/kg）通过渗透微型泵皮下植入治疗博来霉素（Bleomycin）诱导的肺纤维化小鼠，改善了小鼠的肺纤维化，减少了肺泡巨噬细胞数量，降低了支气管肺泡液（BALF）中TGF-β1水平[7]。