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MedKoo CAT#: 205788
Description: RO5126766, also known as CH5126766, is a protein kinase inhibitor specific for the Raf and MEK mitogen-activated protein kinases (MAPKs) with potential anti-neoplastic activity. Raf/MEK dual kinase Inhibitor RO5126766 specifically inhibits the kinase activities of Raf and MEK, resulting in the inhibition of of target gene transcription that promotes malignant transformation of cells. Both Raf and MEK are serine/threonine-specific kinases that respond to extracellular stimuli, such as mitogens, and are involved in the regulation of cellular processes, such as gene expression, mitosis, differentiation, and apoptosis.
MedKoo Cat#: 205788
Chemical Formula: C21H18FN5O5S
Exact Mass: 471.10127
Molecular Weight: 471.46152
Elemental Analysis: C, 53.50; H, 3.85; F, 4.03; N, 14.85; O, 16.97; S, 6.80
Synonym: RO5126766; RO 5126766; RO5126766; CH5126766; CH5126766; CH 5126766.
IUPAC/Chemical Name: 3-[[2-[(Methylaminosulfonyl)amino]-3-fluoropyridin-4-yl]methyl]-4-methyl-7-[(pyrimidin-2-yl)oxy]-2H-1-benzopyran-2-one
InChi Key: LMMJFBMMJUMSJS-UHFFFAOYSA-N
InChi Code: InChI=1S/C21H18FN5O5S/c1-12-15-5-4-14(31-21-25-7-3-8-26-21)11-17(15)32-20(28)16(12)10-13-6-9-24-19(18(13)22)27-33(29,30)23-2/h3-9,11,23H,10H2,1-2H3,(H,24,27)
SMILES Code: O=C1C(CC2=C(F)C(NS(=O)(NC)=O)=NC=C2)=C(C)C3=CC=C(OC4=NC=CC=N4)C=C3O1
Phase I study of RO5126766: RO5126766 is a first-in-class, dual Raf/MEK inhibitor, which was tested in a phase I study. The results showed that RO5126766 had a manageable safety profile. MTD was defined for all regimens and RP2D is 2.7 mg 4/3. Favorable PK/PD profile with encouraging biological and antitumor activity were demonstrated. (source: J Clin Oncol 29: 2011 (suppl; abstr 3006).
1: Miller CR, Oliver KE, Farley JH. MEK1/2 inhibitors in the treatment of gynecologic malignancies. Gynecol Oncol. 2014 Jan 14. pii: S0090-8258(14)00019-5. doi: 10.1016/j.ygyno.2014.01.008. [Epub ahead of print] Review. PubMed PMID: 24434059.
2: Tegnebratt T, Lu L, Lee L, Meresse V, Tessier J, Ishii N, Harada N, Pisa P, Stone-Elander S. [18 F]FDG-PET imaging is an early non-invasive pharmacodynamic biomarker for a first-in-class dual MEK/Raf inhibitor, RO5126766 (CH5126766), in preclinical xenograft models. EJNMMI Res. 2013 Sep 16;3(1):67. doi: 10.1186/2191-219X-3-67. PubMed PMID: 24041012; PubMed Central PMCID: PMC3848680.
3: Honda K, Yamamoto N, Nokihara H, Tamura Y, Asahina H, Yamada Y, Suzuki S, Yamazaki N, Ogita Y, Tamura T. Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013 Sep;72(3):577-84. doi: 10.1007/s00280-013-2228-4. Epub 2013 Jul 17. PubMed PMID: 23860959.
4: Ishii N, Harada N, Joseph EW, Ohara K, Miura T, Sakamoto H, Matsuda Y, Tomii Y, Tachibana-Kondo Y, Iikura H, Aoki T, Shimma N, Arisawa M, Sowa Y, Poulikakos PI, Rosen N, Aoki Y, Sakai T. Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. Cancer Res. 2013 Jul 1;73(13):4050-60. doi: 10.1158/0008-5472.CAN-12-3937. Epub 2013 May 10. PubMed PMID: 23667175.
5: Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013 Apr 12;6:27. doi: 10.1186/1756-8722-6-27. Review. PubMed PMID: 23587417; PubMed Central PMCID: PMC3626705.
6: Kraeber-BodÃ©rÃ© F, Carlier T, Naegelen VM, Shochat E, Lumbroso J, Trampal C, Nagarajah J, Chua S, Hugonnet F, Stokkel M, Gleeson F, Tessier J. Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. J Nucl Med. 2012 Dec;53(12):1836-46. doi: 10.2967/jnumed.112.109421. Epub 2012 Nov 9. PubMed PMID: 23143089.
7: Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber-BodÃ©rÃ© F, Rojo F, Routier E, Guarin E, Xu ZX, Rueger R, Tessier JJ, Shochat E, Blotner S, Naegelen VM, Soria JC. First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012 Sep 1;18(17):4806-19. Epub 2012 Jul 3. PubMed PMID: 22761467.