Ci-1040
2-(2-Chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide
CAS: 212631-79-3
Molecular Formula: C17H14ClF2IN2O2
Ci-1040 - Names and Identifiers
| Name | 2-(2-Chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide |
| Synonyms | CI1040 CS-333 Ci-1040 PD184352 PD-184352 CI 1040 (PD184352) 2-[(2-CHLORO-4-IODOPHENYL) AMINO]-N-(CYCLOPROPYLME 2-(2-CHLORO-4-IODOANILINO)-N-(CYCLOPROPYLMETHOXY)-3,4-DIFLUOROBENZAMIDE 2-(2-Chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide 2-[(2-Chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluorobenzamide Benzamide, 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro- |
| CAS | 212631-79-3 |
| InChI | InChI=1/C17H14ClF2IN2O2/c18-12-7-10(21)3-6-14(12)22-16-11(4-5-13(19)15(16)20)17(24)23-25-8-9-1-2-9/h3-7,9,22H,1-2,8H2,(H,23,24) |
Ci-1040 - Physico-chemical Properties
| Molecular Formula | C17H14ClF2IN2O2 |
| Molar Mass | 478.66 |
| Density | 1.747±0.06 g/cm3(Predicted) |
| Melting Point | 166-169°C |
| Solubility | DMSO: ≥30mg/mL |
| Appearance | powder |
| Color | white to tan |
| pKa | -5.58±0.50(Predicted) |
| Storage Condition | room temp |
| Refractive Index | 1.656 |
| MDL | MFCD02683961 |
| Use | PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor with an IC50 of 17 nM. The selectivity for MEK1/2 is 100 times higher than MEK5. |
| In vitro study | 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 Indication type with GI50 of 1.1 μm. A recent research indications CI-1040 effects of BMS-214662 in CML blast crisis cell line, K562, and in primary chronic phase CD34 + CML cells. CI-1040 treatment reduced 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 cancer cells. CI-1040 treatment did not inhibit the phosphorylation of Jun kinase, p38 kinase or Akt, indicating that CI-1040 is specifically acting on MEK. CI-1040 inhibition of MAPK activation prevents cell cycle progression and induces G1 arrest. The IC50 for CI-1040 inhibition of MEK1 was 0.3 μm, 15-fold higher than the concentration required to inhibit EGF-induced ERK2 activation in Swiss 3T3 cells. These results indicate that CI-1040 exerts an effect on the cells by inhibiting MKK1 activation, but not by blocking MKK1 activity. 2 nM PD184352 inhibited 50% of MKK1 activation in Swiss 3T3 cells, while more than 100-fold concentration of CI-1040 inhibited MEK1 in vitro. PD184352 also inhibited Raf-catalyzed phosphorylation of MEK1, but had no effect on Raf-catalyzed phosphorylation of myelin basic protein. CI-1040 inhibited papillary thyroid carcinoma (PTC) cell growth by 86%, resulting in RET/PTC1 rearrangement at a concentration of 10 μm, compared to cells treated with DMSO only. CI-1040 showed a potent inhibitory effect on PTC cells (BRAF mutation) with a GI50 of 52 nM, but had a lower activity on RET/PTC1 rearrangement with a GI50 of 1.1 μm. A recent study showed a CI-1040 increase in CML BMS-214662 apoptotic effect in blast phase cell lines, K562, and primary chronic phase CD34 + CML cells. |
| In vivo study | 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 Oral administration with a reduction in the phosphate of ERK1/2 and the immuno-reactivity of Ki67 and of CD31 CI-1040 attenuates growth of colon tumor xenografts in mice and humans, there was a broad dose range of 48-200 mg/kg per dose, but no effect on P388 leukemia. CI-1040 after 3 weeks of oral administration (300 mg/kg/d), tumor xenografts from PTC cells were inhibited compared to untreated (vehicle-only) mice, 31.3% fewer grafts carrying BRAF mutations and 47.5% fewer grafts carrying RET/PTC1 rearrangements. No toxic effects were observed when mice were treated with CI-1040. Transient exposure of breast tumors to CI-1040 and UCN-01 causes tumor cell death in vivo and prolonged inhibition of tumor regrowth. CI-1040 (25 mg/kg) and UCN-01 (0.1-0.2 Combination therapy at mg/kg) significantly reduced MDA-MB-231 and largely abolished MCF7 tumor growth implanted into athymic mice, while any single treatment was not significantly active. The combination resulted in significant tumor cell death, consistent with phosphorylation of ERK1/2 and reduced immune activity of Ki67 and cd31. |
Ci-1040 - Risk and Safety
| Hazard Symbols | N - Dangerous for the environment |
| Risk Codes | 50/53 - Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment. |
| Safety Description | S60 - This material and its container must be disposed of as hazardous waste. S61 - Avoid release to the environment. Refer to special instructions / safety data sheets. |
| UN IDs | UN 3077 9 / PGIII |
| WGK Germany | 3 |
Ci-1040 - Preparation solution concentration reference
| 1mg | 5mg | 10mg | |
|---|---|---|---|
| 1 mM | 2.089 ml | 10.446 ml | 20.892 ml |
| 5 mM | 0.418 ml | 2.089 ml | 4.178 ml |
| 10 mM | 0.209 ml | 1.045 ml | 2.089 ml |
| 5 mM | 0.042 ml | 0.209 ml | 0.418 ml |
Last Update：2024-01-02 23:10:35
Ci-1040 - Reference Information
| biological activity | PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM, and its selectivity to MEK1/2 is 100 times higher than MEK5. Phase 2. PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor. IC50 is 17 nM in cell test, and its selectivity to MEK1/2 is 100 times higher than MEK5. PD184352 (CI-1040) can selectively induce apoptosis. Phase 2. |
| in vitro study | 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 don'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 μ M, 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 10 μM compared with cells treated with DMSO only. CI-1040 shows inhibition to PTC cells (BRAF mutation) with GI50 of 52 nM, but low activity to RET/PTC1 rearrangement type with GI50 of 1.1 μ m. a 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. CI-1040 treatment enables multiple tumor cells, including colon 26, BX-PC3 pancreatic cancer, A431 cervical cancer, HT-29 colon cancer, ZR-25-1 decreased pMAPK levels in breast cancer and SKOV-3 ovarian cancer cells. CI-1040 treatment does not inhibit the phosphorylation of Jun kinase, p38 kinase or Akt, which indicates that CI-1040 specifically acts on MEK. CI-1040 inhibition of MAPK activation prevents cell cycle progression and induces G1 phase arrest. The IC50 for CI-1040 inhibition of MEK1 was 0.3 μM, 15-fold higher than the concentration required to inhibit EGF-induced ERK2 activation in Swiss 3T3 cells. These results indicate that CI-1040 works on cells by inhibiting MKK1 activation, rather than by blocking MKK1 activity. 2 nM PD184352 inhibited 50% MKK1 activation in Swiss 3T3 cells, while more than 100-fold concentrations of CI-1040 inhibited MEK1 in vitro. PD184352 also inhibits Raf-catalyzed MEK1 phosphorylation, but has no effect on Raf-catalyzed myelin basic protein phosphorylation. Compared with cells treated with DMSO only, CI-1040 inhibited the growth of 86% papillary thyroid carcinoma (PTC) cells, resulting in RET/PTC1 rearrangement at 10 μM concentration. CI-1040 showed effective inhibition on PTC cells (BRAF mutation) with GI50 of 52 nM, but low activity on RET/PTC1 rearrangement type with GI50 of 1.1 μM. A recent study showed that CI-1040 increased the apoptosis of BMS-214662 in CML acute phase cell line, K562, and primary chronic phase CD34 + CML cells. |
| in vivo study | 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 tumours to CI-1040 and UCN-01 causes tumour cell death in vivo and prolonged suppression of tumour regrowth. Combined treatment CI-1040 (25 mg/kg) and UCN-01 (0.1-0.2 mg/kg) significantly reduces MDA-MB-231, and largely abolishs MCF7 tumour growth in implanted athymic mice, while either single treatment has no significant activity. The drug combination led to profound tumour cell death which correlates with a reduction in the phosphorylation of ERK1/2 and the immuno-reactivity of Ki67 and of CD31. CI-1040 oral administration attenuates the growth of mouse and human colon tumor xenografts, with a wide dose range of 48-200 mg/kg per dose, but it has no effect on P388 leukemia. Inhibition of tumor xenografts from PTC cells after 3 weeks of oral administration of CI-1040 (300 mg/kg/d) resulted in a reduction of 31.3% in grafts carrying the BRAF mutant and 47.5% in grafts carrying the RET/PTC1 rearrangement type compared to untreated (carrier-only) mice. When mice were treated with CI-1040, no toxic effects were observed. Transient exposure of breast tumors to CI-1040 and UCN-01 causes tumor cell death in vivo and prolongs inhibition of tumor regrowth. The combination therapy of CI-1040 (25 mg/kg) and UCN-01 (0.1-0.2 mg/kg) significantly reduced MDA-MB-231 and largely abolished MCF7 tumor growth implanted in athymic mice, while any monotherapy had no significant activity. The combination caused significant tumor cell death, which was consistent with phosphorylation of ERK1/2 and decreased immune activity of Ki67 and CD31. |
| features | first MEK inhibitor to begin clinical development. |
| target | TargetValue MEK1 (cell-free say) 17 nM MEK2 (cell-free say) 17 nM |
| Target | Value |
| MEK1 (Cell-free assay) | 17 nM |
| MEK2 (Cell-free assay) | 17 nM |
Last Update：2024-04-09 01:59:59
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Product Name: PD184352 (CI-1040) Visit Supplier Webpage Request for quotationCAS: 212631-79-3
Tel: 18301782025
Email: 3008007409@qq.com
Mobile: 18021002903
QQ: 3008007409
Wechat: 18301782025
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