212631-79-3
中文名稱
2-[(2-氯-4-碘苯基)氨基]-N-(環(huán)丙基甲氧基)-3,4-二氟-苯甲酰胺
英文名稱
PD184352
CAS
212631-79-3
分子式
C17H14ClF2IN2O2
分子量
478.66
MOL 文件
212631-79-3.mol
更新日期
2024/12/15 19:35:21
212631-79-3 結(jié)構(gòu)式
基本信息
中文別名
MEK小分子抑制劑(CI-1040)2-(2-氯-4-碘苯氨基)-N-(環(huán)丙基甲氧基)-3,4-二氟苯酰胺
2-(2-氯-4-碘苯氨基)-N-(環(huán)丙基甲氧基)-3,4-二氟苯甲酰胺
2-[(2-氯-4-碘苯基)胺]-N-(環(huán)丙基甲氧基)-3,4-二氟苯甲胺
-[(2-氯-4-碘苯基)氨基]-N-(環(huán)丙基甲氧基)-3,4-二氟-苯甲酰胺
2-[(2-氯-4-碘苯基)氨基]-N-(環(huán)丙基甲氧基)-3,4-二氟-苯甲酰胺
英文別名
CS-333Ci-1040
PD184352
PD 184352, >=98%
CI-1040, PD-184352
PD184352 USP/EP/BP
PD 184352
CI-1040
PD-184352
CI1040
PD-184352
CI 1040 (PD184352)
2-[(2-CHLORO-4-IODOPHENYL) AMINO]-N-(CYCLOPROPYLME
2-(2-CHLORO-4-IODOANILINO)-N-(CYCLOPROPYLMETHOXY)-3,4-DIFLUOROBENZAMIDE
所屬類別
生物化工：MEK 抑制劑物理化學(xué)性質(zhì)
熔點166-169°C
密度1.747±0.06 g/cm3(Predicted)
儲存條件-20°C冷凍
儲存條件room temp
溶解度二甲基亞砜：≥30mg/mL
酸度系數(shù)(pKa)-5.58±0.50(Predicted)
形態(tài)粉末
顏色白色至棕褐色
常見問題列表
生物活性
PD184352 (CI-1040)是一種ATP非競爭性的MEK1/2抑制劑，IC50為17 nM，對MEK1/2的選擇性比MEK5高100倍。Phase 2。體外研究
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.體內(nèi)研究
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.特征
First MEK inhibitor to begin clinical development.生物活性
PD184352 (CI-1040) 是一種ATP非競爭性的MEK1/2抑制劑，細(xì)胞試驗中IC50為17 nM，對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。靶點
| Target | Value |
|
MEK1
(Cell-free assay) | 17 nM |
|
MEK2
(Cell-free assay) | 17 nM |
體外研究
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也會抑制Raf催化的MEK1磷酸化，而對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，10μM濃度時導(dǎo)致RET/PTC1重排。CI-1040對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RET/PTC1重排型活性較低，GI50 為1.1 μM。一項最近的研究表明CI-1040增加CML 急變期細(xì)胞系，K562，和初級慢性期CD34+ CML細(xì)胞中BMS-214662的凋亡作用。
體內(nèi)研究
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，具有48-200 mg/kg每劑的廣泛劑量范圍，但是對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，沒有觀察到毒性作用。乳腺腫瘤對CI-1040和UCN-01的瞬時暴露引起腫瘤細(xì)胞體內(nèi)死亡，并延長對腫瘤再生長的抑制。CI-1040 (25 mg/kg) 和UCN-01 (0.1-0.2 mg/kg)的聯(lián)合治療顯著減少MDA-MB-231，并很大程度上廢除植入無胸腺小鼠的MCF7腫瘤生長，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。