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Vemurafenib

Description of Vemurafenib: Vemurafenib (also known as PLX4032, RG7204 or RO5185426, marketed as Zelboraf)  is an orally bioavailable, ATP-competitive, small-molecule inhibitor of BRAF(V600E) kinase with potential antineoplastic activity. Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011. Vemurafenib selectively binds to the ATP-binding site of BRAF(V600E) kinase and inhibits its activity, which may result in an inhibition of an over-activated MAPK signaling pathway downstream in BRAF(V600E) kinase-expressing tumor cells and a reduction in tumor cell proliferation. Approximately 90% of BRAF gene mutations involve a valine-to-glutamic acid mutation at residue 600 (V600E); the oncogene protein product, BRAF(V600E) kinase, exhibits a markedly elevated activity that over-activates the MAPK signaling pathway. The BRAF(V600E) gene mutation has been found to occur in approximately 60% of melanomas, and in about 8% of all solid tumors, including melanoma, colorectal, thyroid and other cancers. Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Currently developer: Plexxikon (now part of the Daiichi Sankyo group) and Hoffmann–La Roch.

Vemurafenib is developed by Plexxikon (now part of the Daiichi Sankyo group) and Hoffmann–La Roche for the treatment of late-stage melanoma. Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011.

Vemurafenib (pronounced vem yoo RAF en ib) is designed to selectively inhibit a cancer-driving mutated form of the BRAF protein. Vemurafenib is being co-developed under a 2006 license and collaboration agreement between Roche/Genentech and Plexxikon. The cobas 4800 BRAF V600 Mutation Test is an investigational, polymerase chain reaction-based companion diagnostic being developed by Roche to identify people whose tumors carry the BRAF V600 mutation.  Vemurafenib - Mechanism of action: Vemurafenib has been shown to cause programmed cell death in melanoma cell lines. Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation. Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have this mutation. Melanoma cells without this mutation are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases. In vitro, a melanoma cell line A375 is inhibited by silencing the BRAF gene by short hairpin RNA. (source: http://en.wikipedia.org/wiki/Vemurafenib).

According to Smalley, Keiran S. M. 's paper, In October 2006, Plexxikon granted Roche a worldwide license to develop and commercialize PLX-4032 and any other anticancer candidates arising from the collaboration. The companies would jointly develop the drug and follow-on compounds, and Plexxikon retained the right to co-promote products from the collaboration in the US. Plexxikon would receive US $40 million upfront and a further US $6 million in research funding for 2 years. Plexxikon could also receive up to US $660 million in milestone payments plus royalties. see Smalley, Keiran S. M. Current Opinion in Investigational Drugs (BioMed Central) (2010), 11(6), 699-706.

Drug information

ZELBORAF (vemurafenib) is a kinase inhibitor available as 240 mg tablets for oral use. Vemurafenib has the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide. It has the molecular formula C23H18ClF2N3O3S and a molecular weight of 489.9. Vemurafenib is a white to off-white crystalline solid. It is practically insoluble in aqueous media. Tablets of ZELBORAF are for oral administration. Each tablet contains 240 mg of vemurafenib. The inactive ingredients of ZELBORAF are: Tablet Core: hypromellose acetate succinate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and hydroxypropyl cellulose. Coating: pinkish white: poly(vinyl alcohol), titanium dioxide, polyethylene glycol 3350, talc, and iron oxide red.  Indication: ZELBORAF™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma.

Mechanism of Action:

Vemurafenib is a low molecular weight, orally available, inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAFV600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FOR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAFV600E.  Pharmacokinetics: The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of dosing at 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. A one-compartment disposition model with first-order absorption and first-order elimination adequately describes the vemurafenib concentration-time profile. At steady state, vemurafenib exhibits linear pharmacokinetics within the 240 mg to 960 mg dose range.

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