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The SARfaris: GPCR, Kinase, ADME

Monday, 22 August 2011

New Drug Approvals 2011 - Pt. XXIV Vemurafenib (Zelboraf TM)

ATC code: L01XE15
Wikipedia: Vemurafenib

On the August 17th 2011, the FDA approved Vemurafenib (trade name:Zelboraf TM Research code: PLX-4032, RG-7204 and RO-5185426), a BRAF kinase inhibitor for the treatment of patients with unresectable or metastatic melanoma carrying the mutant BRAFV600E.

Melanoma is a malignant tumor of melanocytes (skin cells that produce melanin) and is an aggressive disease responsible for an estimated 50,000 deaths worldwide. Over 50% of patients with advanced melanoma carry an activating mutation in the Serine/Theronine protein kinase: BRAF (V600E).
The MAPK signal transduction pathway is an important and frequently mutated pathway in cancer. A wide variety of growth factors signal through this pathway, via RAS and RAF proteins to cause cell proliferation. The activating mutation in BRAF causes activation of this pathway downstream of BRAF regardless of the presence of growth factor (the signalling pathway is 'dysregulated'). The protein of Vemurafenib is this mutant enzyme BRAFV600E (Uniprot:P15056(wt)), although it shows activity in vitro against other protein kinases including such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar affinities.

One side effect observed in nearly a quarter of patients is the paradoxical growth of cutaneous squamous cell carcinomas (cuSCC), a different, and less aggressive type of skin cancer. Intriguingly, this appears to be cause by activating the same pathway in normal cells of the same patient that carry a RAS mutation.


The structure of Vemurafenib complexed to BRAF is known (PDBe:3og7).

Vemurafenib (Molecular formula: C23H18ClF2N3O3S; IUPAC: N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide; Canonical smiles: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(cc23)c4ccc(Cl)cc4)c1F ; standard InChI: 1S/C23H18ClF2N3O3S/c1-2-9-33(31,32)29-19-8-7-18(25)20(21(19)26)22(30)17-12-28-23-16(17)10-14(11-27-23)13-3-5-15(24)6-4-13/h3-8,10-12,29H,2,9H2,1H3,(H,27,28) CHEMBL1229517, Chemspider:24747352, PubChem:CID 42611257). Vemurafenib is a synthetic small molecule drug, with no chiral centres, it has a molecular weight of 489.9 MWt and is fully rule of Five compliant.

Vemurafenib is orally administered as tablets, each tablet contains 240 mg of active compound - dosing is 960 mg twice daily (equivalent to 3920 umol). The bioavailability of vemurafenib has not been determined. Following oral administration of vemurafenib at 960 mg twice daily for 15 days to patients with metastatic melanoma, the median Tmax was approximately 3 hours. Vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor and is a CYP3A4 inducer, it is highly bound to serum albumin and alpha-1 acid glycoprotein (> 99% ppb). In treated patient populations the apparent volume of distribution is 106 L, the clearance is 31 L/day and the median half life is 57 hours. It is largely excreted in feces (94% of dose).

Vemurafenib is also notable in being arguably the first drug discovered and optimised using fragment soaking methods for initial lead discovery. Vemurafenib was discovered in the labs of Plexxikon.

Full US Prescribing information is here

Zelboraf is marketed by Hoffmann-La Roche Inc.

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