B-Raf inhibitor 1 - CAS 1093100-40-3
Catalog number: 1093100-40-3
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
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B-Raf inhibitor 1 is a potent and selective B-Raf inhibitor with cell IC50s of 0.31 μM and 2 nM for A375 proliferation and A375 p-ERK respectively.
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1.Mutant B-Raf(V600E) Promotes Melanoma Paracellular Transmigration by Inducing Thrombin-mediated Endothelial Junction Breakdown.
Zhang P1, Feng S2, Liu G3, Wang H3, Zhu H2, Ren Q2, Bai H2, Fu C4, Dong C4. J Biol Chem. 2016 Jan 29;291(5):2087-106. doi: 10.1074/jbc.M115.696419. Epub 2015 Oct 26.
Tumor invasiveness depends on the ability of tumor cells to breach endothelial barriers. In this study, we investigated the mechanism by which the adhesion of melanoma cells to endothelium regulates adherens junction integrity and modulates tumor transendothelial migration (TEM) by initiating thrombin generation. We found that the B-Raf(V600E) mutation in metastatic melanoma cells up-regulated tissue factor (TF) expression on cell membranes and promoted thrombin production. Co-culture of endothelial monolayers with metastatic melanoma cells mediated the opening of inter-endothelial spaces near melanoma cell contact sites in the presence of platelet-free plasma (PFP). By using small interfering RNA (siRNA), we demonstrated that B-Raf(V600E) and TF silencing attenuated the focal disassembly of adherens junction induced by tumor contact. Vascular endothelial-cadherin (VE-cadherin) disassembly was dependent on phosphorylation of p120-catenin on Ser-879 and VE-cadherin on Tyr-658, Tyr-685, and Tyr-731, which can be prevented by treatment with the thrombin inhibitor, hirudin, or by silencing the thrombin receptor, protease-activated receptor-1, in endothelial cells.
2.Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma.
Williams TE1, Subramanian S1, Verhagen J1, McBride CM1, Costales A1, Sung L1, Antonios-McCrea W1, McKenna M1, Louie AK1, Ramurthy S1, Levine B1, Shafer CM1, Machajewski T1, Renhowe PA1, Appleton BA1, Amiri P1, Chou J1, Stuart D1, Aardalen K1, Poon D1. ACS Med Chem Lett. 2015 Aug 3;6(9):961-5. doi: 10.1021/ml500526p. eCollection 2015.
Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.
3.Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling.
Liu L1, Lee MR2, Kim JL3, Whittington DA3, Bregman H4, Hua Z4, Lewis RT4, Martin MW4, Nishimura N5, Potashman M4, Yang K5, Yi S4, Vaida KR4, Epstein LF3, Babij C6, Fernando M6, Carnahan J6, Norman MH5. Bioorg Med Chem. 2016 May 15;24(10):2215-34. doi: 10.1016/j.bmc.2016.03.055. Epub 2016 Apr 13.
One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/αC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf(V600E)/B-Raf(WT) biochemical ((b)S), cellular ((c)S) selectivity, and the phospho-ERK activation ((p)A). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf(V600E) selectivity.
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CAS 1093100-40-3 B-Raf inhibitor 1

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