PD184352 (CI-1040)是一種ATP非競(jìng)爭(zhēng)性的MEK1/2抑制劑，IC50為17 nM，對(duì)MEK1/2的選擇性比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) 是一種ATP非競(jìng)爭(zhēng)性的MEK1/2抑制劑，細(xì)胞試驗(yàn)中IC50為17 nM，對(duì)MEK1/2的選擇性比MEK5高100倍。PD184352 (CI-1040)可選擇性地誘導(dǎo)凋亡。Phase 2。

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

CI-1040治療使多重腫瘤細(xì)胞，包括結(jié)腸26，BX-PC3 胰腺癌，A431 子宮頸癌，HT-29結(jié)腸癌， ZR-25-1乳腺癌和SKOV-3 卵巢癌細(xì)胞中pMAPK 水平降低。CI-1040治療不抑制Jun激酶，p38 激酶或Akt的磷酸化作用，這表明CI-1040特定作用于MEK。CI-1040對(duì)MAPK活化的抑制阻止細(xì)胞周期進(jìn)程，并誘導(dǎo)G1期阻滯。 CI-1040抑制MEK1的IC50為0.3 μM，比抑制Swiss 3T3細(xì)胞中EGF誘導(dǎo)的ERK2活化所需的濃度高15倍。這些結(jié)果表明CI-1040通過抑制MKK1活化，而不是通過阻斷MKK1活性對(duì)細(xì)胞發(fā)揮作用。2 nM PD184352抑制Swiss 3T3細(xì)胞中50%的MKK1活化，而超過100倍濃度的CI-1040在體外抑制MEK1。PD184352也會(huì)抑制Raf催化的MEK1磷酸化，而對(duì)Raf催化的髓鞘堿性蛋白磷酸化沒有作用。與僅用DMSO處理的細(xì)胞相比，CI-1040抑制86%甲狀腺乳頭狀癌(PTC)細(xì)胞生長(zhǎng)，10μM濃度時(shí)導(dǎo)致RET/PTC1重排。CI-1040對(duì)PTC細(xì)胞(BRAF 突變)表現(xiàn)出有效的抑制作用，GI50為52 nM，但是對(duì)RET/PTC1重排型活性較低，GI50 為1.1 μM。一項(xiàng)最近的研究表明CI-1040增加CML 急變期細(xì)胞系，K562，和初級(jí)慢性期CD34+ CML細(xì)胞中BMS-214662的凋亡作用。

CI-1040口服給藥減弱小鼠和人結(jié)腸腫瘤異種移植物的生長(zhǎng)，具有48-200 mg/kg每劑的廣泛劑量范圍，但是對(duì)P388白血病沒有作用。 CI-1040口服給藥(300 mg/kg/d)3周后，抑制來自PTC細(xì)胞的腫瘤異種移植物，與未處理的(僅載體處理)小鼠相比，使攜帶BRAF突變型的移植物減少31.3%，攜帶RET/PTC1重排型的移植物減少47.5%。小鼠用CI-1040處理時(shí)，沒有觀察到毒性作用。乳腺腫瘤對(duì)CI-1040和UCN-01的瞬時(shí)暴露引起腫瘤細(xì)胞體內(nèi)死亡，并延長(zhǎng)對(duì)腫瘤再生長(zhǎng)的抑制。CI-1040 (25 mg/kg) 和UCN-01 (0.1-0.2 mg/kg)的聯(lián)合治療顯著減少M(fèi)DA-MB-231，并很大程度上廢除植入無胸腺小鼠的MCF7腫瘤生長(zhǎng)，而任何單一治療都沒有顯著活性。聯(lián)合用藥引起顯著的腫瘤細(xì)胞死亡，這與ERK1/2的磷酸化和Ki67與CD31的免疫活性降低相一致。