FTI 277 HCl

FTI 277 HCl is a potent and selective farnesyltransferase (FTase) inhibitor with an IC₅₀ value of 0.5nM, exhibiting approximately 100-fold greater selectivity over geranylgeranyltransferase I (GGTase I)^[1]. FTase-mediated farnesylation is the first irreversible and rate-limiting step for Ras membrane association, and is an obligatory modification for the biological activity of oncogenic Ras^[2]. FTI 277 HCl is commonly used in research on the function of farnesyltransferase and the role of Ras-mediated signaling pathways in diseases such as cancer^[3,4].

In vitro, treatment of vascular smooth muscle cells (VSMCs) with FTI 277 HCl (20μM) for 10 days significantly inhibited β-glycerophosphate (βGP)-induced mineral deposition, reduced the mRNA expression of Runx2 and Msx2, and up-regulated the expression of MGP^[5]. Pretreatment of breast cancer MDA-MB-231 cells with FTI 277 HCl (50μM) for 24h inhibited epidermal growth factor (EGF)-induced activation of H-Ras in the membrane fraction, but did not inhibit the activation of N-Ras^[6].

In vivo, administration of FTI 277 HCl (1 and 5mg/kg/day) via intraperitoneal injection in SCID mice inoculated with human colon cancer HT29 cells for 3 weeks significantly reduced relative spleen weight and primary splenic tumor volume, as well as relative liver weight and liver metastasis volume, without causing significant toxicity^[7]. In mice treated with FTI 277 HCl (25mg/kg) via intraperitoneal injection before L-arginine-induced pancreatitis, samples were harvested 72h after the first dose of L-arginine. FTI 277 HCl administration significantly reduced L-arginine-induced myeloperoxidase (MPO) levels and the number of extravascular neutrophils in the pancreas^[8].

References:
[1] LERNER E C, QIAN Y, BLASKOVICH M A, et al. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes[J]. Journal of Biological Chemistry, 1995, 270(45): 26802-26806.
[2] COX A D, DER C J, PHILIPS M R. Targeting RAS membrane association: back to the future for anti-RAS drug discovery?[J]. Clinical Cancer Research, 2015, 21(8): 1819-1827.
[3] MAZZOCCA A, GIUSTI S, HAMILTON A D, et al. Growth inhibition by the farnesyltransferase inhibitor FTI-277 involves Bcl-2 expression and defective association with Raf-1 in liver cancer cell lines[J]. Molecular Pharmacology, 2003, 63(1): 159-166.
[4] BERNHARD E J, KAO G, COX A D, et al. The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts[J]. Cancer Research, 1996, 56(8): 1727-1730.
[5] PONNUSAMY A, SINHA S, HYDE G D, et al. FTI-277 inhibits smooth muscle cell calcification by up-regulating PI3K/Akt signaling and inhibiting apoptosis[J]. PLoS One, 2018, 13(4): e0196232.
[6] LEE K H, KOH M, MOON A. Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation[J]. Oncology Letters, 2016, 12(3): 2222-2226.
[7] NAM J S, INO Y, SAKAMOTO M, et al. Ras farnesylation inhibitor FTI-277 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis[J]. Japanese Journal of Cancer Research, 2002, 93(9): 1020-1028.
[8] MERZA M, AWLA D, HWAIZ R, et al. Farnesyltransferase regulates neutrophil recruitment and tissue damage in acute pancreatitis[J]. Pancreas, 2014, 43(3): 427-435.

FTI 277 HCl是一种强效且具有选择性的法尼基转移酶（FTase）抑制剂，IC₅₀值为0.5nM，较香叶酰基香叶转移酶I（GGTase I）选择性高出约100倍^[1]。FTase 法尼基化是 Ras 膜缔合的第一个不可逆的限速步骤，也是致癌 Ras 生物活性的专性修饰^[2]。FTI 277 HCl通常用于法尼基转移酶功能及Ras介导的信号通路在癌症等疾病中作用机制的研究^[3,4]。

在体外，FTI 277 HCl（20μM）处理血管平滑肌细胞（VSMC）10天，显著抑制了β-甘油磷酸盐（βGP）诱导的矿物质沉积，并降低了Runx2和Msx2的mRNA表达，同时上调了MGP的表达^[5]。FTI 277 HCl（50μM）预处理乳腺癌MDA-MB-231细胞24h，抑制了表皮生长因子（EGF）诱导的H-Ras在膜组分中的激活，但不抑制 N-Ras 的激活^[6]。

在体内，FTI 277 HCl（1 and 5mg/kg/day）通过腹腔注射治疗接种了人结肠癌HT29细胞的SCID小鼠，3周后显著降低了脾脏相对重量和脾原发肿瘤体积，也显著降低了相对肝脏重量和肝转移体积，且未引起明显毒性^[7]。FTI 277 HCl（25mg/kg）在L-精氨酸诱导胰腺炎前腹腔注射处理小鼠，在第一次服用 L-精氨酸后 72 h收获样品，FTI 277 HCl的给药显著降低了L-精氨酸诱发的髓过氧化物酶（MPO）水平和胰腺中血管外中性粒细胞的数量^[8]。