<p style=/line-height:25px/>Dabrafenib Mesylate(GSK-2118436 Mesylate) is a novel, potent, and selective Raf kinase inhibitor that is capableof inhibiting the kinase activity of wild-type B-Raf, B-RafV600Eand c-Raf with IC50 values of 3.2, 0.8, and 5.0 nM, respectively.<br>IC50 Value: 3.2/0.8/5.0 nM (B-Raf/B-RafV600E/ c-Raf) [1]<br>Target: B-RafV600E<br>in vitro: Dabrafenib is a novel, potent, and selective Raf kinase inhibitor that is capableof inhibiting the kinase activity of wild-type B-Raf, B-RafV600Eand c-Raf with IC50 values of 3.2, 0.8, and 5.0 nM, respectively.Kinase panel screening for over 270 kinases has indicated that this inhibitor is selective for Raf kinase, with 400 fold selectivitytowards B-Raf over 91% of the other kinases tested. Specificcellular inhibition of B-RafV600E kinase by this inhibitor leadsto decreased ERK phosphorylation and inhibition of cell proliferationby an initial arrest in the G1 phase of the cell cycle, followedby cell death. This inhibition is selective for cancer cellsthat specifically encode the mutation for B-RafV600E [1]. The combination of GSK2118436 and GSK1120212 effectively inhibited cell growth, decreased ERK phosphorylation, decreased cyclin D1 protein, and increased p27(kip1) protein in the resistant clones. Moreover, the combination of GSK2118436 or GSK1120212 with the phosphoinositide 3-kinase/mTOR inhibitor GSK2126458 enhanced cell growth inhibition and decreased S6 ribosomal protein phosphorylation in these clones [2].<br>in vivo: Oral compoundadministration inhibits the growth of B-RafV600E mutant melanoma(A375P) and colon cancer (Colo205) human tumor xenografts, growingsubcutaneously in immuno-compromised mice [1]. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose [3].<br>Toxicity: Treatment-related adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma (five [6%] patients in cohort A, of whom one also had keratoacanthoma; six [7%] in cohort B). Four grade 4 treatment-related adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial haemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten [6%] patients), intracranial haemorrhage (ten [6%]; one treatment-related), and squamous-cell carcinoma (11 [6%]) [4].<br>Clinical trial: BREAK-2: A Study of GSK-2118436 in Previously Treated BRAF Mutant Metastatic Melanoma. Phase 2<br></p>
