Wnt-C59 is a highly potent inhibitor of Porcupine (Porcn), a member of the Mboat (membrane-bound O-acyl deglycosylase) family, with an IC50 value of 74pM, and can inhibit Wnt signaling[1]. The Wnt signaling pathway is a complex network of proteins whose functions are most commonly seen in embryonic development and cancer, but are also involved in normal physiological processes in adult animals[2]. Wnt-C59 has the potential to eradicate cancer stem cells (CSCs) in human tumors[3]. Wnt-C59 can be used to induce human pluripotent stem cells (IPSCs) to differentiate into cortical motor neurons (CMNs) or their progenitors[4].
In vitro, Wnt-C59 (0.01, 1μM) treatment of NIH 3T3 fibroblasts for 48h significantly induced the expression of genes related to hypertrophy (BNP) and fibrosis (COL1 and COL3) in the cells[5]. Wnt-C59 (10μM) treatment of human fetal liver progenitor cells (HFLPC) significantly inhibited cell migration and proliferation induced by Wnt3a and Wnt5a[6].
In vivo, Wnt-C59 (5mg/kg) was orally treated for 4 weeks in cardiac hypertrophy model mice, which significantly improved the cardiac function and survival rate of mice, and attenuated the transverse aortic constriction (TAC)-induced cardiac mass, increase in cardiomyocyte cross-sectional area, cardiac fibrosis, cardiomyocyte apoptosis, and expression of hypertrophic biomarkers β-MHC, ANP, and BNP[7]. Wnt-C59 (40, 60mg/kg) was intraperitoneally treated in mice with endotoxin-induced sepsis, which significantly improved the survival rate of mice and reduced the lethality and plasma levels of proinflammatory cytokines and organ damage biomarkers[8].
References:
[1] Shah K, Panchal S, Patel B. Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway[J]. Pharmacological research, 2021, 167: 105532.
[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] Cheng Y, Phoon Y P, Jin X, et al. Wnt-C59 arrests stemness and suppresses growth of nasopharyngeal carcinoma in mice by inhibiting the Wnt pathway in the tumor microenvironment[J]. Oncotarget, 2015, 6(16): 14428.
[4] Motono M, Ioroi Y, Ogura T, et al. WNT-C59, a small-molecule WNT inhibitor, efficiently induces anterior cortex that includes cortical motor neurons from human pluripotent stem cells[J]. Stem cells translational medicine, 2016, 5(4): 552-560.
[5] Paul M A, Wainwright C L, Hector E E, et al. Short‐Term Oral Administration of the Porcupine Inhibitor, Wnt‐c59, Improves the Structural and Functional Features of Experimental HFpEF[J]. Pharmacology Research & Perspectives, 2025, 13(1): e70054.
[6] Liu Z, Kuna V K, Xu B, et al. Wnt ligands 3a and 5a regulate proliferation and migration in human fetal liver progenitor cells[J]. Translational Gastroenterology and Hepatology, 2021, 6.
[7] Zhao Z, Liu H, Li Y, et al. Wnt-C59 attenuates pressure overload-induced cardiac hypertrophy via interruption of wnt pathway[J]. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 2020, 26: e923025-1.
[8] Jang J, Song J, Sim I, et al. Wnt-Signaling Inhibitor Wnt-C59 suppresses the cytokine upregulation in multiple organs of lipopolysaccharide-induced endotoxemic mice via reducing the interaction between β-Catenin and NF-κB[J]. International Journal of Molecular Sciences, 2021, 22(12): 6249.
Wnt-C59是Mboat（膜结合的O-酰脱糖酶）家族成员Porcupine（Porcn）的高度有效抑制剂，IC50值为74pM，能够抑制Wnt信号传导[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]。Wnt-C59具有根除人类肿瘤中癌症干细胞（CSC）的潜力[3]。Wnt-C59能够用于诱导人多能干细胞（IPSC）分化为皮质运动神经元（CMN）或其祖细胞[4]。
在体外，Wnt-C59（0.01, 1μM）处理NIH 3T3成纤维细胞48h，显著诱导了细胞中与肥大有关的基因（BNP）和纤维化（COL1和COL3）的表达[5]。Wnt-C59（10μM）处理人胎儿肝祖细胞（HFLPC），显著抑制了Wnt3a和Wnt5a诱导的细胞迁移和增殖[6]。
在体内，Wnt-C59（5mg/kg）通过口服治疗心脏肥大模型小鼠4周，显著改善了小鼠的心脏功能并提高了其存活率，减弱了横向主动脉收缩（TAC）手术诱导的心脏质量、心肌细胞横截面积的增加、心脏纤维化、心肌细胞凋亡以及肥大性生物标志物β-MHC、ANP和BNP的表达[7]。Wnt-C59（40，60mg/kg）通过腹腔注射治疗内毒素诱导的败血症小鼠，显著提高了小鼠的存活率，降低了促炎细胞因子和器官破坏生物标志物的致死性和血浆水平[8]。