Vemurafenib

Structural formula
General
Non-proprietary name	Vemurafenib
other names	PLX4032 RG7204 RO5185426
Molecular formula	C 23 H 18 ClF 2 N 3 O 3 S
External identifiers / databases
CAS number 918504-65-1 1029872-54-5 PubChem 42611257 DrugBank DB08881 Wikidata Q423111
properties
Molar mass	489.92 g mol −1
safety instructions
GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Vemurafenib is the international non-proprietary name for a synthetically produced chemical compound from the group of sulfonamides . In August 2011, the drug with protein kinase inhibitor activity was approved under the trade name Zelboraf for the treatment of malignant melanoma in the USA. The substance was developed by Roche and Plexxikon . Plexxikon was bought by Daiichi-Sankyo in April 2011 so that these two companies jointly market Zelboraf.

Mechanism of action

Vemurafenib is a selective inhibitor of the oncogene B-Raf , a serine / threonine kinase . The oncogene B-Raf is activated in the tumor cells in a number of cancers. In malignant melanoma this is the case in about 70%, in thyroid cancer in 30 to 70%, in ovarian cancer in 15 to 30% and in colorectal cancer in 5 to 20% of the diseases. Mutations in B-Raf cause increased kinase activity, which leads to overactivation of the mitogen-activated protein kinase pathway. In model organisms with xenografted malignant melanomas, Vemurafenib deactivated B-Raf and regression of the tumors was observed. The deactivation of B-Raf causes apoptosis in the tumor cells .

About 50% of human malignant melanomas have the V600E mutation in B-Raf. Vemurafenib is only effective in this genotype. In this type of mutation, glutamic acid (E) is built into the B-Raf protein in position 600 instead of valine (V) . From the results of early clinical studies (phase I and II), a time-limited response of the tumor to the active ingredient was found in some patients, i.e., after a certain period of treatment, the tumor cells become resistant to vemurafenib. A “switch” of the tumor cells to a different signal path is suspected to be the cause of the development of resistance. For example, increased expression of PDGFRB (a platelet-derived growth factor receptor) was observed in some cells with resistance development , which led to an alternative path of survival (instead of B-Raf). In other resistant cells, activation of the oncogene NRAS (neuroblastoma- RAS ) was found, which reactivates the normal B-RAF survival path.

The IC ₅₀ compared to V600E mutants is 44 nmol / L, while it is over 2.4 µmol / L in wild-type cells .

Side effects

In August 2013, the manufacturer Roche drew attention to the risk of progression of malignant diseases and drug rash with eosinophilia and systemic symptoms (DRESS syndrome) in connection with Zelboraf® (vemurafenib) in a Rote-Hand-Brief .

Combination with and radiation therapy for melanoma can lead to cutis verticis gyrata .

Admission

In August 2011, the US Food and Drug Administration (FDA) approved Zelboraf ^® (vemurafenib) for the treatment of patients with inoperable or metastatic melanoma and a BRAF V600 mutation., Followed in February 2012 by the EU Commission for the European market. In Germany, the Institute for Quality and Efficiency in Health Care ( IQWiG ) examined the additional benefit of vemurafenib. Accordingly, there are considerable advantages in terms of overall survival compared with dacarbazine, but serious side effects. Overall, there is an indication of a considerable added benefit.

Vemurafenib is currently in clinical phase II in patients with malignant melanoma with brain metastases .

further reading

• KS Smalley: PLX-4032, a small molecule B-Raf inhibitor for the potential treatment of malignant melanoma. In: Current Opinion in Investigational Drugs Volume 11, Number 6, June 2010, pp. 699-706, PMID 20496265 . (Review).
• CA Pratilas, DB Solit: Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. In: Clinical Cancer Research Volume 16, Number 13, July 2010, pp. 3329-3334, doi : 10.1158 / 1078-0432.CCR-09-3064 . PMID 20472680 . PMC 291221 (free full text). (Review).
• C. Shepherd, I. Puzanov, JA Sosman: B-RAF inhibitors: an evolving role in the therapy of malignant melanoma. In: Current Oncology Reports Volume 12, Number 3, May 2010, pp. 146-152, doi : 10.1007 / s11912-010-0095-2 . PMID 20425073 . (Review).
• C. Wellbrock, A. Hurlstone: BRAF as therapeutic target in melanoma. In: Biochemical Pharmacology Volume 80, Number 5, September 2010, pp. 561-567, doi : 10.1016 / j.bcp.2010.03.019 . PMID 20350535 . (Review).

Web links

• Malignant Melanoma - New Hope for Skin Cancer Patients. In: Focus Online , July 15, 2011

Individual evidence

1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
2. ^ Plexxikon Announces European Approval of Zelboraf (R) for the Treatment of Patients with BRAF Mutation-Positive Metastatic Melanoma , press release by Daiichi-Sankyo of February 20, 2012, accessed on September 6, 2013.
3. ↑ New drugs: Zelboraf ^® (vemurafenib) (PDF; 123 kB) Information from the drug commission of the German medical profession (AkdÄ), as of June 12, 2012.
4. ↑ European Medicines Agency (EMA): Zelboraf EPAR - Summary for the public, accessed on September 6, 2013 (English).
5. ^ EMA: Summary of the EPAR for the public (PDF; 113 kB) accessed on September 6, 2013 (German).
6. ↑ ^{a b c} E. Sala, L. Mologni, S. Truffa, C. Gaetano, GE Bollag, C. Gambacorti-Passerini: BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells . ( Memento of the original from February 2, 2016 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. In: Molecular Cancer Research Volume 6, Number 5, May 2008, pp. 751-759, doi : 10.1158 / 1541-7786.MCR-07-2001 . PMID 18458053 . 
7. ^ E. Livingstone, L. Zimmer, S. Piel, D. Schadendorf: PLX4032: does it keep its promise for metastatic melanoma treatment? In: Expert Opinion on Investigational Drugs Volume 19, Number 11, November 2010, pp. 1439–1449, doi : 10.1517 / 13543784.2010.527945 . PMID 20942773 . (Review).
8. ↑ R. Nazarian, H. Shi, Q. Wang, X. Kong, RC Koya, H. Lee, Z. Chen, MK Lee, N. Attar, H. Sazegar, T. Chodon, SF Nelson, G. McArthur, JA Sosman, A. Ribas, RS Lo: Melanomas acquire resistance to B-RAF (V600E) inhibition by RTK or N-RAS upregulation. In: Nature Volume 468, Number 7326, December 2010, pp. 973-977, doi : 10.1038 / nature09626 . PMID 21107323 .
9. ↑ R. Halaban, W. Zhang, A. Bacchiocchi, E. Cheng, F. Parisi, p Ariyan, M. Krauthammer, JP McCusker, Y. Kluger, M. Sznol: PLX4032, a selective BRAF (V600E) kinase inhibitor , activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. In: Pigment Cell & Melanoma Research Volume 23, Number 2, April 2010, pp. 190-200, doi : 10.1111 / j.1755-148X.2010.00685.x . PMID 20149136 . PMC 284897 (free full text).
10. ↑ Red Hand Letter from Roche on August 30, 2013. (PDF; 127 kB) Accessed September 5, 2013 . 
11. ↑ emedicine
12. ↑ FDA grants approval for Zelboraf (vemurafenib) and companion test for BRAF mutation-positive metastatic melanoma, a deadly form of skin cancer , Roche press release of August 22, 2011
13. ↑ NZZ Online Roche receives EU approval for skin cancer drug published on February 27, 2012 Link .
14. ↑ Anna-Sabine Ernst: Indication of considerable additional benefit of vemurafenib in advanced melanoma. Institute for Quality and Efficiency in Health Care (IQWiG), press release from June 15, 2012 at Informationsdienst Wissenschaft (idw-online.de), accessed on August 24, 2015.
15. ↑ Clinical Study (Phase II): A Study of Vemurafenib in Metastatic Melanoma Patients With Brain Metastases at Clinicaltrials.gov of the NIH

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