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Vemurafenib

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This is an old revision of this page, as edited by Rod57 (talk | contribs) at 15:14, 7 June 2011 (→‎Clinical trials: June 2011 positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.<ref). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Vemurafenib
Clinical data
Routes of
administration		Oral
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider
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ECHA InfoCard100.287.801 Edit this at Wikidata
Chemical and physical data
FormulaC23H18ClF2N3O3S
Molar mass489.92 g/mol g·mol−1
3D model (JSmol)
  • CCCS(=O)(=O)Nc1ccc(c(c1F)C(=O)c2c[nH]c3c2cc(cn3)c4ccc(cc4)Cl)F
  • 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) checkY
  • Key:GPXBXXGIAQBQNI-UHFFFAOYSA-N checkY
  (verify)
Crystallographic structure of B-Raf (rainbow colored, N-terminus = blue, C-terminus = red) complexed with PLX4032 (spheres, carbon = white, oxygen = red, nitrogen = blue, chlorine = green, fluorine = cyan, sulfur = yellow).[1]

PLX4032 (also known as vemurafenib, RG7204 or RO5185426) is a B-Raf enzyme inhibitor that is being developed by Plexxikon and Hoffmann–La Roche for the treatment of late-stage melanoma.[1]

Mechanism of action

PLX4032 has been shown to cause programmed cell death in melanoma cell lines.[2] PLX4032 interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation.

PLX4032 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 the V600E BRAF mutation. Melanoma cells without this mutation are not inhibited by PLX4032; PLX4032 paradoxically stimulates normal BRAF and may promote tumor growth.[3][4]

In vitro, a melanoma cell line A375 is inhibited by silencing the BRAF gene by short hairpin RNA.[2]

Resistance

Two mechanisms of resistance to PLX4032 (covering 40% of cases) have been discovered :

  • the cancer cells begin to overexpress a cell surface protein PDGFRB creating an alternate survival pathway
  • a second oncogene called NRAS mutates, reactivating the normal BRAF survival pathway.[5]

Clinical trials

In a phase I clinical study, PLX4032 was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma, and the treated group had a median increased survival time of 6 months over the control group.[6][7][8][9] A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. However the regression only lasted from 2 to 18 months.[10]

Phase I[11] and phase II studies are ongoing,[12] and a phase III trial has been started.[13]

In 2010 it was also in phase I trials for colorectal cancer.[11]

In June 2011 positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.[14] Further trials are planned incluing with a MEK-inhibitor GDC-0973.[14]

Side effects

At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal.[1]

References

  1. ^ a b c PDB: 3OG7​; Bollag G, Hirth P, Tsai J; et al. (2010). "Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma". Nature. 467 (7315): 596–599. doi:10.1038/nature09454. PMC 2948082. PMID 20823850. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C (2008). "BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells". Mol. Cancer Res. 6 (5): 751–9. doi:10.1158/1541-7786.MCR-07-2001. PMID 18458053. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S (2010). "RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth". Nature. 464 (7287): 431–5. doi:10.1038/nature08833. PMID 20130576. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M (2010). "PLX4032, a Selective BRAF(V600E) Kinase Inhibitor, Activates the ERK Pathway and Enhances Cell Migration and Proliferation of BRAF(WT) Melanoma Cells". Pigment Cell Melanoma Res. 23 (2): 190–200. doi:10.1111/j.1755-148X.2010.00685.x. PMC 2848976. PMID 20149136. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (2010). "Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation". Nature. 468 (7326): 973–977. doi:10.1038/nature09626. PMID 21107323. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ "Drug hope for advanced melanoma". BBC News. 2009-06-02. Retrieved 2009-06-07.
  7. ^ Harmon A (2010-02-21). "Target Cancer - A Roller Coaster Chase for a Cure". NY Times. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  8. ^ Garber K (2009). "Cancer research. Melanoma drug vindicates targeted approach". Science. 326 (5960): 1619. doi:10.1126/science.326.5960.1619. PMID 20019269. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Flaherty K, Puzanov I, Sosman J, Kim K, Ribas A, McArthur G, Lee RJ, Grippo JF, Nolop K, Chapman P. "Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. - ASCO". 2009 ASCO Annual Meeting Abstract, J Clin Oncol 27:15s, 2009 (suppl; abstr 9000). {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)CS1 maint: multiple names: authors list (link)
  10. ^ Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010). "Inhibition of mutated, activated BRAF in metastatic melanoma". N. Engl. J. Med. 363 (9): 809–19. doi:10.1056/NEJMoa1002011. PMID 20818844. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ a b "Safety Study of PLX4032 in Patients With Solid Tumors - Full Text View -". NCT00405587. ClinicalTrials.gov. 2009-10-28. Retrieved 2010-02-23. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  12. ^ "A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma". NCT00949702. ClinicalTrials.gov. 2010-02-15. Retrieved 2010-02-23. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  13. ^ "First Patient Dosed In Phase 3 Trial Of PLX4032 (RG7204) For Metastatic Melanoma". Press Release. Plexxikon. 2010-01-08. Retrieved 2010-03-04. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  14. ^ a b "Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study". 6 June 2011.
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