Ac-Gly-BoroPro

Ac-Gly-BoroPro is a selective Fibroblast Activation Protein (FAP) inhibitor with a Ki of 23nM^{[1, 2]}. Ac-Gly-BoroPro selectively inhibits FAP, compared to other proline peptidases^{[3, 4]}, which is an important biomarker for cancer-associated fibroblasts and activated fibroblasts. FAP reacts readily with submicromolar concentrations of Ac-Gly-BoroPro, reaching steady state inhibition levels rapidly (Ki=23±3nM)^[2].

Ac-Gly-BoroPro (10μM; 24h or 48h) can inhibit Human periodontal ligament stem cells (hPDLSCs) proliferation and migration^[5]. Ac-Gly-BoroPro (20μM; 7 days) can inhibit osteoclast differentiation^[6].

Ac-Gly-BoroPro (500μg/kg; 35 days; intraperitoneal injection) was administered to 2-month-old unmated female mice with ovariectomized ovaries, which could alleviate osteoporosis induced by ovariectomy, promote bone formation, and inhibit bone resorption in mice^[6]. Ac-Gly-BoroPro (40μg/kg; 4 weeks; intra-articular injection) could significantly improve cartilage erosion, subchondral bone thickening and osteophyte formation in destabilization of the medial meniscus (DMM) mice model^[7].

References:
[1] HENDERSON J M, XIANG M S W, HUANG J C, et al. Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma [J]. Cancers (Basel), 2021, 13(21):
[2] HU Y, MA L, WU M, et al. Synthesis and structure-activity relationship of N-alkyl Gly-boro-Pro inhibitors of DPP4, FAP, and DPP7 [J]. Bioorg Med Chem Lett, 2005, 15(19): 4239-42.
[3] ZHAO L, CHEN J, PANG Y, et al. Fibroblast activation protein-based theranostics in cancer research: A state-of-the-art review [J]. Theranostics, 2022, 12(4): 1557-69.
[4] KIM S M, JANG Y J. Enzymatic activity of fibroblast activation protein-alpha is essential for TGF-beta1-induced fibroblastic differentiation of human periodontal ligament cells [J]. Exp Cell Res, 2024, 442(2): 114230.
[5] HE J, FANG B, SHAN S, et al. Mechanical stiffness promotes skin fibrosis through FAPalpha-AKT signaling pathway [J]. J Dermatol Sci, 2024, 113(2): 51-61.
[6] WEI H, XU Y, WANG Y, et al. Identification of Fibroblast Activation Protein as an Osteogenic Suppressor and Anti-osteoporosis Drug Target [J]. Cell Rep, 2020, 33(2): 108252.
[7] FAN A, WU G, WANG J, et al. Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression [J]. Bone Res, 2023, 11(1): 3.

Ac-Gly-BoroPro是一种选择性成纤维细胞活化蛋白（FAP）抑制剂，Ki为23nM^{[1, 2]}。相较于其他脯氨酸肽酶，Ac-Gly-BoroPro选择性抑制FAP^{[3, 4]}，FAP是癌症相关成纤维细胞和活化成纤维细胞的重要生物标志物。FAP很容易与亚微摩尔浓度的Ac-Gly-BoroPro反应，迅速达到稳态抑制水平（Ki=23±3nM）^[2]。

Ac-Gly-BoroPro（10μM；24小时或48小时）可以抑制人牙周膜干细胞 （hPDLSCs）的增殖和迁移^[5]。Ac-Gly-BoroPro（20μM；7天）可抑制破骨细胞的分化^[6]。

使用Ac-Gly-BoroPro（500μg/kg; i.p. ; 35 days）处理2月龄切除卵巢的未交配雌性小鼠，Ac-Gly-BoroPro能够减轻卵巢切除所致的骨质疏松症，促进小鼠的骨形成，抑制骨吸收^[6]。使用Ac-Gly-BoroPro（40μg/kg; intra-articular injection; 4 weeks）处理DMM（Destabilization of the medial meniscus; 内侧半月板失稳）模型小鼠能够显著改善小鼠的软骨糜烂、软骨下骨增厚和骨赘形成^[7]。