ABC99 is an N-hydroxyhydantoin (NHH)-carbamate-based, irreversible and selective inhibitor of Wnt-deacylating enzyme NOTUM[1]. NOTUM is a secreted serine hydrolase that negatively modulates Wnt/β-catenin signaling by removing the essential palmitoleate moiety from Wnt proteins[2]. ABC99 is usually used in models of osteoporosis, colorectal cancer and neurodegenerative diseases where Wnt signaling is insufficient[3][4].
In vitro, ABC99 (2µg/mL; 7–14 days) suppressed odontoblastic differentiation of human stem cells from apical papilla (hSCAPs), reduced ALP activity, blocked mineralized nodule formation, and decreased DSPP, DMP1 and ALP mRNA levels[5]. ABC99 (50nM and 500nM; 14 days) significantly reversed the inhibition of osteogenic differentiation of hPDLSCs by recombinant human NOTUM, restored ALP activity and calcium nodule formation, and increased the protein/mRNA levels of Osterix, OCN and Runx2[6].
In vivo, ABC99 (10mg/kg/day; p.o.; 4 weeks) almost completely prevented liver metastasis and lymph-node metastasis, reduced primary tumor weight, and significantly inhibited Ki67⁺ cell proliferation in orthotopic colorectal cancer mice[7].
References:
[1] Suciu RM, Cognetta AB 3rd, Potter ZE, Cravatt BF. Selective Irreversible Inhibitors of the Wnt-Deacylating Enzyme NOTUM Developed by Activity-Based Protein Profiling. ACS Med Chem Lett. 2018;9(6):563-568.
[2] Bayle ED, Svensson F, Atkinson BN, et al. Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling. J Med Chem. 2021;64(8):4289-4311.
[3] Zhao Y, Jolly S, Benvegnu S, Jones EY, Fish PV. Small-molecule inhibitors of carboxylesterase Notum. Future Med Chem. 2021;13(11):1001-1015.
[4] Larrick JW, Mendelsohn AR. Roads to the Fountain of Youth? Rejuvenating Intestinal Stem Cells. Rejuvenation Res. 2019;22(4):342-347.
[5] Zhao Q, Ren H, Wang N, Yuan X, Zhao Y, Wen Q. NOTUM plays a bidirectionally modulatory role in the odontoblastic differentiation of human stem cells from the apical papilla through the WNT/β-catenin signaling pathway. Arch Oral Biol. 2024;160:105896.
[6] Yang P, Li C, Kou Y, et al. Notum suppresses the osteogenic differentiation of periodontal ligament stem cells through the Wnt/Beta catenin signaling pathway. Arch Oral Biol. 2021;130:105211.
[7] Tian Y, Wang X, Cramer Z, et al. APC and P53 mutations synergise to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer. Gut. 2023;72(12):2294-2306.
ABC99 是一种N-羟基海因（NHH）-氨基甲酸酯类、不可逆的Wnt去酰基化酶NOTUM选择性抑制剂[1]。NOTUM是一种分泌型丝氨酸水解酶，通过去除Wnt蛋白的必需棕榈酰基团来负向调控Wnt/β-catenin信号通路[2]。ABC99常用于骨质疏松、结直肠癌及神经退行性疾病等 Wnt 信号不足模型研究[3][4]。
在体外，ABC99（2µg/mL；7–14天）抑制人根尖乳头干细胞（hSCAPs）的成牙本质向分化，降低碱性磷酸酶（ALP）活性，阻断矿化结节形成，并降低牙本质涎磷蛋白（DSPP）、牙本质基质蛋白1（DMP1）和ALP的mRNA水平[5]。ABC99（50nM 和 500nM；14天）显著逆转重组人NOTUM对人牙周膜干细胞（hPDLSCs）成骨分化的抑制，恢复ALP活性和钙结节形成，并增加Osterix、骨桥蛋白（OCN）和骨钙素（Runx2）的蛋白/mRNA水平[6]。
在体内，ABC99（10mg/kg/天；口服；4周）几乎完全阻断了原位结直肠癌小鼠模型中的肝脏转移和淋巴结转移，降低了原发肿瘤的重量，并显著抑制了 Ki67⁺细胞增殖[7]。