BGJ398 (Infigratinib)

BGJ398 (Infigratinib)は経口で、ATP競合性の汎FGFRチロシンキナーゼ阻害剤である（FGFR1: IC₅₀ = 0.9nM; FGFR2: IC₅₀ = 1.4nM; FGFR3: IC₅₀ = 1nM; FGFR4: IC₅₀ = 60nM）^[1]。BGJ398は線維芽細胞成長因子受容体FGFR1、FGFR2、FGFR3とFGFR4を標的とし、よってこれらの受容体で媒介されたシグナル伝導を遮断し、FGFR依存性の腫瘍細胞増殖と血管新生を阻害する^[2-3]。BGJ398は主に、子供の小人症の治療に使われる^[4]。

SKOV3ip1細胞で、球状体培養における細胞の生存率は、BGJ398 (0.3125-5µM；72時間)処理の後、著しく減少した^[5]。UMUC-14細胞で、パクリタキセルとBGJ398 (0-10µM；72時間)の併用は、細胞アポトーシスの促進で相乗効果を産生できる^[6]。

TMK-1細胞異種移植マウスモデルで、BGJ398 (10mg/kg；経口投与；20日間)の処理は、腫瘍の成長を著しく阻害した^[7]。Snu16R由来の異種移植マウスモデルで、BAG3のノックダウンは、BGJ398 (30mg/kg；経口投与；4週間)による抗腫瘍作用を増強する^[8]。

References:
[1]. Guagnano V, Furet P, Spanka C, et al. Discovery of 3-(2, 6-dichloro-3, 5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase[J]. Journal of medicinal chemistry, 2011, 54(20): 7066-7083.
[2]. Szymczyk J, Sluzalska K D, Materla I, et al. FGF/FGFR-dependent molecular mechanisms underlying anti-cancer drug resistance[J]. Cancers, 2021, 13(22): 5796.
[3]. Agrawal S, Maity S, AlRaawi Z, et al. Targeting drugs against fibroblast growth factor (s)-induced cell signaling[J]. Current drug targets, 2021, 22(2): 214-240.
[4]. Högler W, Ward L M. New developments in the management of achondroplasia[J]. Wiener Medizinische Wochenschrift, 2020, 170(5): 104-111.
[5]. Cha H J, Choi J H, Park I C, et al. Selective FGFR inhibitor BGJ398 inhibits phosphorylation of AKT and STAT3 and induces cytotoxicity in sphere-cultured ovarian cancer cells[J]. International Journal of Oncology, 2017, 50(4): 1279-1288.
[6]. Kim S H, Ryu H, Ock C Y, et al. BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression[J]. International journal of molecular sciences, 2018, 19(10): 3164.
[7]. Schmidt K, Moser C, Hellerbrand C, et al. Targeting fibroblast growth factor receptor (FGFR) with BGJ398 in a gastric cancer model[J]. Anticancer Research, 2015, 35(12): 6655-6665.
[8]. Li K, Deng X, Feng G, et al. Knockdown of Bcl-2-associated athanogene-3 can enhance the efficacy of BGJ398 via suppressing migration and inducing apoptosis in gastric cancer[J]. Digestive Diseases and Sciences, 2021, 66(9): 3036-3044.