Lonafarnib (Sch66336) is an orally bioavailable FPTase inhibitor for H-ras, K-ras-4B, and N-ras (IC50: 1.9/5.2/2.8 nM).

N-Ras:2.8 nM, H-Ras:1.9 nM, KRas-4B:5.2 nM

SCH66336在0.1 μM至8 μM的浓度范围内，以剂量和时间依赖的方式抑制人头颈部鳞状细胞癌细胞(HNSCC)的生长并诱导凋亡。SCH66336（8 μM）抑制蛋白激酶B/Akt活性及其底物糖原合成激酶（GSK）-3β、叉头转录因子和BAD在SqCC/Y1细胞中的磷酸化。[2] SCH66336对细胞系表现出不同的抗增殖效果，IC50范围为0.6 μM至32.3 μM。[3] Lonafarnib通过CCAAT/增强子结合蛋白同源蛋白（CHOP）-依赖的方式激活DR5启动子的转录活化，从而诱导CHOP依赖性DR5上调。Lonafarnib（<10 μM）激活caspase-8及其下游caspases，因而在H1792细胞中诱导基于caspase-8的凋亡。Lonafarnib（5 μM）上调DR5表达，增加细胞表面DR5分布，并增强肿瘤坏死因子相关凋亡诱导配体诱导的凋亡。[4]

Lonafarnib以剂量依赖的方式抑制裸鼠体内HTBI77人肺癌异种移植瘤的生长。[1] 通过口腔灌注，每日两次以50 mg/kg剂量给药的Lonafarnib，能在携带s.c.侧翼XEN01、XEN05或XEN08 GBM异种移植瘤的NOD/SCID小鼠中，经过21天的治疗后抑制肿瘤生长，达到最高69%的生长抑制。[3]

FPTactivity is determined by measuring the transfer of [3H]farnesyl from [3H]farnesyl PPi to trichloroacetic acid-precipitable Ha-Ras-CVLS. GGPT-1 activity is similarly determined using [3H]geranylgeranyl diphosphate and Ha-Ras-CVLL as substrates[1].

The cells are seeded in 96-well cell-culture cluster plates at a density that allowed control cultures to grow exponentially for 5 days. After 24 hours, the cells are treated with different concentrations of SCH66336. SCH66336 is dissolved in DMSO. Control cultures received the same amount of DMSO as the treated cultures do. Cell numbers are estimated after 5 days of treatment by SRB assay. The percentage of growth inhibition is calculated by using the equation: percentage growth inhibition = (1 ? At/Ac) × 100, where At and Ac represent the absorbance in treated and control cultures, respectively. The drug concentration causing a 50% cell growth inhibition (IC50), is determined by interpolation from dose-response curves.(Only for Reference)