Skip to main content

New Drug Approvals 2011 - Pt. X Vandetanib (ZactimaTM)

Image
By Bissan Al-Lazikani







ATC code: L01XE12

On the 6th April 2011, the FDA approved Vandetanib (trade name: ZactimaTM, ATC code: L01XE12, NDA 022405), a multi-kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. (medullary thyroid cancer; CRUK Thyroid cancer; ICD C73) Medullary thyroid cancer is a rare form of Thyroid cancer, but is associated with poorer prognosis. While the primary tumor can be successfully removed using surgery and radiotherapy, and thus can have a high 5 and 10 year survival rate (>90%), the metastatic disease remains challenging and is has a low 40% survival rate. Medullary thyroid cancer can be a sporadic or hereditary disease, and has complex underlying genetic causes. Approximately 25% of cases are associated with the RET (REarranged during Transfection) proto-oncogene. RET mutations cause Multiple Endocrine Neoplasia type 2 (MEN 2) which increases the risk of Thyroid cancer. (see OMIM for MEN 2A and MEN 2B)

Vandetanib (also known as ZD-6474 and Trade name:ZactimaTM) ( IUPAC:N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine); InChI:1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27) SMILES:COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC4CCN(C)CC4 ChEMBL:24828; ) It has the molecular formula C22H24BrFN4O2 and has a molecular weight of 475.36. It has no chiral centres. Vandetanib contains an aminoquinazoline, a very common group within a large number of protein kinase inhibitors - this mimics the adenine ring of ATP.

Vandetanib has been issued with a black box warning because it can prolong QT interval (the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. A prolonged QT interval is a biomarker for ventricular tachyarrhythmias like torsades de pointes and a risk factor for sudden death.) For this reason, Vandetanib should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome.

Vandetanib tablets for daily oral administration are available in two dosage strengths, 100 mg and 300 mg, containing 100 mg and 300 mg of vandetanib, respectively. The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterized by a mean clearance (Cl) of approximately 13.2 L/h, a mean volume of distribution of approximately 7450 L, and a median plasma half-life (T1/2) of 19 days.

Vandetanib has a broad activity profile, showing activity against multiple tyrosine kinases including RET (Uniprot: P07949; canSAR Target Synopsis) , EGFR (Uniprot: P00533; canSAR Target Synopsis), FGFR1 (Uniprot: P11362; canSAR Target Synopsis), FGFR2 (Uniprot: P21802; canSAR Target Synopsis), FGFR3 (Uniprot: P22607; canSAR Target Synopsis), and many others, all of which are members of the Protein Tyrosine Kinase family (PFAM:Pkinase_Tyr (PF07714)). RET mutations associated with medullary thyroid cancer include C634R germline mutation in exon 11 and an additional somatic mutation (at chromosomal position 164761.0012), but the efficacy of Vandetanib is independent of the mutation status of RET. A complex structure of Vandetanib bound to RET is available (PDB code: 2ivu @PDBe)

The prescribing information can be found here. 

Vandetanib is a product of AstraZeneca
Labels:

Comments

Post a Comment

Popular posts from this blog

Here's a nice Christmas gift - ChEMBL 35 is out!

By
Use your well-deserved Christmas holidays to spend time with your loved ones and explore the new release of ChEMBL 35!            This fresh release comes with a wealth of new data sets and some new data sources as well. Examples include a total of 14 datasets deposited by by the ASAP ( AI-driven Structure-enabled Antiviral Platform) project, a new NTD data se t by Aberystwyth University on anti-schistosome activity, nine new chemical probe data sets, and seven new data sets for the Chemogenomic library of the EUbOPEN project. We also inlcuded a few new fields that do impr ove the provenance and FAIRness of the data we host in ChEMBL:  1) A CONTACT field has been added to the DOCs table which should contain a contact profile of someone willing to be contacted about details of the dataset (ideally an ORCID ID; up to 3 contacts can be provided). 2) In an effort to provide more detailed information about the source of a deposited dat...
Post a Comment
Read more

Improvements in SureChEMBL's chemistry search and adoption of RDKit

By Eloy
    Dear SureChEMBL users, If you frequently rely on our "chemistry search" feature, today brings great news! We’ve recently implemented a major update that makes your search experience faster than ever. What's New? Last week, we upgraded our structure search engine by aligning it with the core code base used in ChEMBL . This update allows SureChEMBL to leverage our FPSim2 Python package , returning results in approximately one second. The similarity search relies on 256-bit RDKit -calculated ECFP4 fingerprints, and a single instance requires approximately 1 GB of RAM to run. SureChEMBL’s FPSim2 file is not currently available for download, but we are considering generating it periodicaly and have created it once for you to try in Google Colab ! For substructure searches, we now also use an RDKit -based solution via SubstructLibrary , which returns results several times faster than our previous implementation. Additionally, structure search results are now sorted by...
Post a Comment
Read more

ChEMBL 34 is out!

By
We are delighted to announce the release of ChEMBL 34, which includes a full update to drug and clinical candidate drug data. This version of the database, prepared on 28/03/2024 contains:         2,431,025 compounds (of which 2,409,270 have mol files)         3,106,257 compound records (non-unique compounds)         20,772,701 activities         1,644,390 assays         15,598 targets         89,892 documents Data can be downloaded from the ChEMBL FTP site:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/ Please see ChEMBL_34 release notes for full details of all changes in this release:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/chembl_34_release_notes.txt New Data Sources European Medicines Agency (src_id = 66): European Medicines Agency's data correspond to EMA drugs prior to 20 January 2023 (excluding ...
Post a Comment
Read more

Improved querying for SureChEMBL

By
    Dear SureChEMBL users, Earlier this year we ran a survey to identify what you, the users, would like to see next in SureChEMBL. Thank you for offering your feedback! This gave us the opportunity to have some interesting discussions both internally and externally. While we can't publicly reveal precisely our plans for the coming months (everything will be delivered at the right time), we can at least say that improving the compound structure extraction quality is a priority. Unfortunately, the change won't happen overnight as reprocessing 167 millions patents takes a while. However, the good news is that the new generation of optical chemical structure recognition shows good performance, even for patent images! We hope we can share our results with you soon. So in the meantime, what are we doing? You may have noticed a few changes on the SureChEMBL main page. No more "Beta" flag since we consider the system to be stable enough (it does not mean that you will never ...
Post a Comment
Read more

ChEMBL brings drug bioactivity data to the Protein Data Bank in Europe

By
In the quest to develop new drugs, understanding the 3D structure of molecules is crucial. Resources like the Protein Data Bank in Europe (PDBe) and the Cambridge Structural Database (CSD) provide these 3D blueprints for many biological molecules. However, researchers also need to know how these molecules interact with their biological target – their bioactivity. ChEMBL is a treasure trove of bioactivity data for countless drug-like molecules. It tells us how strongly a molecule binds to a target, how it affects a biological process, and even how it might be metabolized. But here's the catch: while ChEMBL provides extensive information on a molecule's activity and cross references to other data sources, it doesn't always tell us if a 3D structure is available for a specific drug-target complex. This can be a roadblock for researchers who need that structural information to design effective drugs. Therefore, connecting ChEMBL data with resources like PDBe and CSD is essen...
Post a Comment
Read more