2-[(2-氯-4-碘苯基)氨基]-N-(环丙基甲氧基)-3,4-二氟-苯甲酰胺

PD184352 (CI-1040)是一种ATP非竞争性的MEK1/2抑制剂，IC50为17 nM，对MEK1/2的选择性比MEK5高100倍。Phase 2。 CI-1040 treatment produces a reduction of pMAPK levels in multiple tumor cells including Colon 26, BX-PC3 pancreatic, A431 cervical, HT-29 colon, ZR-25-1 breast and SKOV-3 ovarian carcinomas. CI-1040 treatment doesn't inhibit the phosphorylation of Jun kinase, p38 kinase or Akt, indicating CI-1040 specifically targets MEK. Inhibition of MAPK activation by CI-1040 prevents cell cycle progression and induces a G1 block. The IC50 for inhibition of MEK1 by CI-1040 is 0.3 μM, 15-fold higher than the concentration required to inhibit the EGF-induced activation of ERK2 in Swiss 3T3 cells. These results indicate CI-1040 exerts its effects on cells by suppressing the activation of MKK1, and not by blocking its activity. 2 nM PD184352 inhibits the activation of MKK1 in Swiss 3T3 cells by 50%, while over 100-fold concentration of CI-1040 inhibits MEK1 in vitro. PD184352 also inhibits the Raf-catalysed phosphorylation of MEK1 without any effect on the Raf-catalysed phosphorylation of myelin basic protein. CI-1040 inhibits 86% of papillary thyroid carcinoma (PTC) cell growth with the RET/PTC1 rearrangement at 10μM compared with cells treated with DMSO only. CI-1040 shows potent inhibition to PTC cells (BRAF mutation) with GI50 of 52 nM, but low activity to RET/PTC1 rearrangement type with GI50 of 1.1 μM. A recent research indicates CI-1040 increases the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. Oral dosing of CI-1040 impairs the growth of colon tumor xenografts of mouse and human with a wide dose range of 48-200 mg/kg per dose, but not of P388 leukemia. CI-1040 inhibits the tumor xenografts from PTC cells carrying a BRAF mutation with 31.3% reduction, carrying the RET/PTC1 rearrangement with 47.5% reduction than in untreated (vehicle) mice after 3 weeks of oral administration (300 mg/kg/d). No toxic effects are observed in any mice when they are treated with CI-1040. Transient exposure of mammary tumors to CI-1040 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth. Combined treatment with CI-1040 (25 mg/kg) and UCN-01 (0.1-0.2 mg/kg) significantly reduces MDA-MB-231, and largely abolishs MCF7 tumor growth in implanted athymic mice, while either single treatment has no significant activity. The drug combination leads to profound tumor cell death which correlates with a reduction in the phosphorylation of ERK1/2 and the immuno-reactivity of Ki67 and of CD31. First MEK inhibitor to begin clinical development. PD184352 (CI-1040) 是一种ATP非竞争性的MEK1/2抑制剂，细胞试验中IC50为17 nM，对MEK1/2的选择性比MEK5高100倍。PD184352 (CI-1040)可选择性地诱导凋亡。Phase 2。

Target	Value
MEK1 (Cell-free assay)	17 nM
MEK2 (Cell-free assay)	17 nM

CI-1040治疗使多重肿瘤细胞，包括结肠26，BX-PC3 胰腺癌，A431 子宫颈癌，HT-29结肠癌， ZR-25-1乳腺癌和SKOV-3 卵巢癌细胞中pMAPK 水平降低。CI-1040治疗不抑制Jun激酶，p38 激酶或Akt的磷酸化作用，这表明CI-1040特定作用于MEK。CI-1040对MAPK活化的抑制阻止细胞周期进程，并诱导G1期阻滞。 CI-1040抑制MEK1的IC50为0.3 μM，比抑制Swiss 3T3细胞中EGF诱导的ERK2活化所需的浓度高15倍。这些结果表明CI-1040通过抑制MKK1活化，而不是通过阻断MKK1活性对细胞发挥作用。2 nM PD184352抑制Swiss 3T3细胞中50%的MKK1活化，而超过100倍浓度的CI-1040在体外抑制MEK1。PD184352也会抑制Raf催化的MEK1磷酸化，而对Raf催化的髓鞘碱性蛋白磷酸化没有作用。与仅用DMSO处理的细胞相比，CI-1040抑制86%甲状腺乳头状癌(PTC)细胞生长，10μM浓度时导致RET/PTC1重排。CI-1040对PTC细胞(BRAF 突变)表现出有效的抑制作用，GI50为52 nM，但是对RET/PTC1重排型活性较低，GI50 为1.1 μM。一项最近的研究表明CI-1040增加CML 急变期细胞系，K562，和初级慢性期CD34+ CML细胞中BMS-214662的凋亡作用。

CI-1040口服给药减弱小鼠和人结肠肿瘤异种移植物的生长，具有48-200 mg/kg每剂的广泛剂量范围，但是对P388白血病没有作用。 CI-1040口服给药(300 mg/kg/d)3周后，抑制来自PTC细胞的肿瘤异种移植物，与未处理的(仅载体处理)小鼠相比，使携带BRAF突变型的移植物减少31.3%，携带RET/PTC1重排型的移植物减少47.5%。小鼠用CI-1040处理时，没有观察到毒性作用。乳腺肿瘤对CI-1040和UCN-01的瞬时暴露引起肿瘤细胞体内死亡，并延长对肿瘤再生长的抑制。CI-1040 (25 mg/kg) 和UCN-01 (0.1-0.2 mg/kg)的联合治疗显著减少MDA-MB-231，并很大程度上废除植入无胸腺小鼠的MCF7肿瘤生长，而任何单一治疗都没有显著活性。联合用药引起显著的肿瘤细胞死亡，这与ERK1/2的磷酸化和Ki67与CD31的免疫活性降低相一致。