3,4-difluoro-2-(2-fluoro-4-iodophenylaMino)-N-(2-hydroxyethoxy)-5-((3-oxoMorpholino)Methyl)benzaMide
3,4-difluoro-2-(2-fluoro-4-iodophenylaMino)-N-(2-hydroxyethoxy)-5-((3-oxoMorpholino)Methyl)benzaMide Basic information
- Product Name:
- 3,4-difluoro-2-(2-fluoro-4-iodophenylaMino)-N-(2-hydroxyethoxy)-5-((3-oxoMorpholino)Methyl)benzaMide
- Synonyms:
-
- 3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxo-2-oxazinanyl)methyl]benzamide
- CH4987655(RO4987655)
- 3,4-difluoro-2-(2-fluoro-4-iodophenylaMino)-N-(2-hydroxyethoxy)-5-((3-oxoMorpholino)Methyl)benzaMide
- RO4987655(CH4987655)
- 2-((2,4-difluorophenyl)aMino)-3,4-difluoro-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2-yl)Methyl)benzaMide
- 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2-yl)methyl]benzamide
- CH-4987655
- CS-1468
- CAS:
- 874101-00-5
- MF:
- C20H19F3IN3O5
- MW:
- 565.28
- Mol File:
- 874101-00-5.mol
3,4-difluoro-2-(2-fluoro-4-iodophenylaMino)-N-(2-hydroxyethoxy)-5-((3-oxoMorpholino)Methyl)benzaMide Chemical Properties
- Density
- 1.740±0.06 g/cm3(Predicted)
- storage temp.
- Store at -20°C
- solubility
- insoluble in H2O; insoluble in EtOH; ≥56.6 mg/mL in DMSO
- form
- solid
- pka
- 14.19±0.10(Predicted)
- color
- White to off-white
3,4-difluoro-2-(2-fluoro-4-iodophenylaMino)-N-(2-hydroxyethoxy)-5-((3-oxoMorpholino)Methyl)benzaMide Usage And Synthesis
Uses
RO4987655 is an orally active and highly selective MEK inhibitor with an IC50 of 5.2 nM for inhibition of MEK1/MEK2.
Biological Activity
ro4987655 is a highly selective and small molecule inhibitor of mek with ic50 value of 5nm [1].ro4987655 is developed with a unique 3-oxo-[1,2]oxazinan-2-ylmethyl group at the 5-position.it is highly selective against mek over other 400 kinases. meanwhile, ro4987655 is a non- competitive inhibitor of mek. it shows higher affinity for mek both in the absence and the presence of atp. ro4987655 has a strong anti-proliferation efficacy in various tumor cells including colo205, ht29, qg56, mia and c32 with ic50 values of 0.86nm, 1.7nm, 9.5nm, 3.3nm and 8.4nm, respectively. in addition, ro4987655 is found to have antitumor activity in a wide range of human cancer xenograft models. in the ht-29 human colon cancer xenograft, ro4987655 shows a strong inhibition of perk formation as well as tumor regression [1, 2].ro4987655 is now in phase i trials. it shows clinical activity in both patients with braf wild-type melanoma and braf v600-mutated melanoma. it is also efficacious in patients with kras-mutated non-small cell lung cancer but not kras-mutated colorectal cancer [2].
in vivo
Single-agent oral administration of RO4987655 (CH4987655) results in complete tumor regressions in xenograft models. RO4987655 is rapidly absorbed with a tmax of ~1 h. Exposures are dose proportional from 0.5 to 4 mg. The disposition is biphasic with a terminal t1/2 of ~25 hr. Intersubject variability is low, 9% to 23% for Cmax and 14% to 25% for area-under-the-curve (AUC). pERK inhibition is exposure dependent and is greater than 80% inhibition at higher doses. The pharmacokinetic-pharmacodynamic relationship is characterized by an inhibitory Emax model (Emax ~100%; IC50 40.6 ng/mL) using nonlinear mixed-effect modeling[1]. Female athymic nude mice are randomized into study groups. The tumors size is estimated with digital caliper and PET scans performed on days 0, 1, and 3 with 1.0, 2.5, and 5.0 mg/kg RO4987655. The vehicle treatment does not inhibit the NCI-H2122 tumor xenograft growth over this time frame. In contrast, RO4987655 treatment results in 119% tumor growth inhibition (TGI) at 1.0 mg/kg, 145% TGI at 2.5 mg/kg and 150% TGI at 5.0 mg/kg on day 3. PET imaging shows that [18F] FDG uptake in the xenografts decreases within 24 h (day 1) from the administration of RO4987655[2].
IC 50
MEK1: 5.2 nM (IC50); MEK2: 5.2 nM (IC50)
References
[1] isshiki y, kohchi y, iikura h, matsubara y, asoh k, murata t, kohchi m, mizuguchi e, tsujii s, hattori k, miura t, yoshimura y, aida s, miwa m, saitoh r, murao n, okabe h, belunis c, janson c, lukacs c, schück v, shimma n. design and synthesis of novel allosteric mek inhibitor ch4987655 as an orally available anticancer agent. bioorg med chem lett. 2011 mar 15;21(6):1795-801.
[2] zimmer l, barlesi f, martinez-garcia m, dieras v, schellens jh, spano jp, middleton mr, calvo e, paz-ares l, larkin j, pacey s, venturi m, kraeber-bodere f, tessier jj, eberhardt we, paques m, guarin e, meresse naegelen v, soria jc. phase i expansion and pharmacodynamic study of the oral mek inhibitor ro4987655 (ch4987655) in selected advanced cancer patients with ras-raf mutations. clin cancer res. 2014 jun 19. pii: clincanres.0341.2014.
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