SP-13786

SP-13786は、線維芽細胞活性化タンパク質（FAP）とプロリルオリゴペプチダーゼ（PREP）の有力で高選択性の阻害剤である（FAP: IC₅₀ = 3.2nM; PREP: IC₅₀ = 1.8μM）^[1]。SP-13786は、FAPの触媒部位と結合することで、FAPのセリンプロテアーゼ活性を阻害し、よって腫瘍間質または線維組織でFAPの機能を阻害する^[2]。SP-13786は、腫瘍、線維症とその他の病理学的なプロセスにおけるFAPの役割の研究に使われる^[3-4]。

MGC803細胞で、SP-13786 (10μM；24時間)の共同培養は、クレシルバイオレット(CV)-FAPの抗腫瘍活性を著しく減らした^[5]。U87MG-Fluc細胞で、SP-13786 (50μM、100μM；30分間)は細胞内FAPのレベルを減らす^[6]。

BALB/cマウスで、SP-13786 (10mg/kg；静脈内注射；単回注射)はFAPα活性を標的とし、阻害する^[7]。心筋梗塞（MI）マウスモデルで、SP-13786 (0.5mg/kg；腹腔内注射；7日間)はFAPを阻害し、心臓の機能を著しく改善し、MI後の血管新生を促進する^[8]。

References:
[1]. Jansen K, Heirbaut L, Verkerk R, et al. Extended structure–activity relationship and pharmacokinetic investigation of (4-quinolinoyl) glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP)[J]. Journal of medicinal chemistry, 2014, 57(7): 3053-3074.
[2]. Kiani M, Jokar S, Hassanzadeh L, et al. Recent clinical implications of FAPI: imaging and therapy[J]. Clinical nuclear medicine, 2022: 10.1097.
[3]. Butuzova D A, Kulebyakina M A, Basalova N A, et al. Fibroblast Activation Protein Alpha (FAPα) as a Promising Target in the Diagnostics and Treatment of Cancer and Fibrotic Diseases: Recent Approaches to Imaging and Assessment of Functional Activity[J]. Biochemistry (Moscow), 2025, 90(Suppl 1): S135-S145.
[4]. Zhou Y, Yin K, Dong H, et al. Long-lasting bioluminescence imaging of the fibroblast activation protein by an amphiphilic block copolymer-based probe[J]. Analytical Chemistry, 2021, 93(8): 3726-3732.
[5]. Liu S Y, Wang H, Nie G. Ultrasensitive fibroblast activation protein-α-activated fluorogenic probe enables selective imaging and killing of melanoma in vivo[J]. ACS sensors, 2022, 7(7): 1837-1846.
[6]. Lin Y, Ma Z, Li Z, et al. Bioluminescent probe for monitoring endogenous fibroblast activation protein-alpha[J]. Analytical Chemistry, 2019, 91(23): 14873-14878.
[7]. Fu A, Wang H, Huo T, et al. A novel chemiluminescence probe for sensitive detection of fibroblast activation protein-alpha in vitro and in living systems[J]. Analytical Chemistry, 2021, 93(16): 6501-6507.
[8]. Sun Y, Ma M, Cao D, et al. Inhibition of fap promotes cardiac repair by stabilizing BNP[J]. Circulation research, 2023, 132(5): 586-600.