Skip to main content

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








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

Comments

Popular posts from this blog

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

ChEMBL 29 Released

  We are pleased to announce the release of ChEMBL 29. This version of the database, prepared on 01/07/2021 contains: 2,703,543 compound records 2,105,464 compounds (of which 2,084,724 have mol files) 18,635,916 activities 1,383,553 assays 14,554 targets 81,544 documents Data can be downloaded from the ChEMBL FTP site:   https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29 .  Please see ChEMBL_29 release notes for full details of all changes in this release: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29/chembl_29_release_notes.txt New Deposited Datasets EUbOPEN Chemogenomic Library (src_id = 55, ChEMBL Document IDs CHEMBL4649982-CHEMBL4649998): The EUbOPEN consortium is an Innovative Medicines Initiative (IMI) funded project to enable and unlock biology in the open. The aims of the project are to assemble an open access chemogenomic library comprising about 5,000 well annotated compounds covering roughly 1,000 different proteins, to synthesiz

Julia meets RDKit

Julia is a young programming language that is getting some traction in the scientific community. It is a dynamically typed, memory safe and high performance JIT compiled language that was designed to replace languages such as Matlab, R and Python. We've been keeping an an eye on it for a while but we were missing something... yes, RDKit! Fortunately, Greg very recently added the MinimalLib CFFI interface to the RDKit repertoire. This is nothing else than a C API that makes it very easy to call RDKit from almost any programming language. More information about the MinimalLib is available directly from the source . The existence of this MinimalLib CFFI interface meant that we no longer had an excuse to not give it a go! First, we added a BinaryBuilder recipe for building RDKit's MinimalLib into Julia's Yggdrasil repository (thanks Mosè for reviewing!). The recipe builds and automatically uploads the library to Julia's general package registry. The build currently targe

Identifying relevant compounds in patents

  As you may know, patents can be inherently noisy documents which can make it challenging to extract drug discovery information from them, such as the key targets or compounds being claimed. There are many reasons for this, ranging from deliberate obfuscation through to the long and detailed nature of the documents. For example, a typical small molecule patent may contain extensive background information relating to the target biology and disease area, chemical synthesis information, biological assay protocols and pharmacological measurements (which may refer to endogenous substances, existing therapies, reaction intermediates, reagents and reference compounds), in addition to description of the claimed compounds themselves.  The SureChEMBL system extracts this chemical information from patent documents through recognition of chemical names, conversion of images and extraction of attached files, and allows patents to be searched for chemical structures of interest. However, the curren

New Drug Warnings Browser

As mentioned in the announcement post of  ChEMBL 29 , a new Drug Warnings Browser has been created. This is an updated version of the entity browsers in ChEMBL ( Compounds , Targets , Activities , etc). It contains new features that will be tried out with the Drug Warnings and will be applied to the other entities gradually. The new features of the Drug Warnings Browser are described below. More visible buttons to link to other entities This functionality is already available in the old entity browsers, but the button to use it is not easily recognised. In the new version, the buttons are more visible. By using those buttons, users can see the related activities, compounds, drugs, mechanisms of action and drug indications to the drug warnings selected. The page will take users to the corresponding entity browser with the items related to the ones selected, or to all the items in the dataset if the user didn’t select any. Additionally, the process of creating the join query is no