ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Monday, 28 September 2009

New Drug Approvals - Pt. XVIII - Ustekinumab (Stelara)

Recently approved by the FDA, on September 25th 2009, was Ustekinumab, marketed under the trade name Stelara. Ustekinumab, previously known as CNTO-1275, is a first-in-class injectable biological drug blocking signalling of two distinct interleukins (IL-12 and IL-23) and is indicated for the treatment of adults with moderate to severe plaque psoriasis. Psoriasis (ICD-10: L40) is a complex autoimmune disease, typically leading to the formation of scaly red or silvery-white plaques on the skin. Another drug with the same mechanism as Ustekinumab (blocking IL-12 and IL-23 signalling) is ABT-874, ABT-874 is currently still in clinical trials.
Ustekinumab is dosed as a subcutaneous injection given at weeks 0 and 4, followed subsequently by every-12-week maintenance dosing. The recommended starting dose of is 45 mg for patients weighing 100 kg or less, and 90 mg for patients weighing more than 110 kg (the 45mg dose corresponds to a 0.31 umol dose).
Ustekinumab is is a human IgG1қ monoclonal antibody and is the first drug to target IL-12 and IL-23 cytokines, these are two naturally occurring secreted, heterodimeric proteins (two distinct proteins (themselves derived from two distinct genes) bound in a specific complex), they are involved in inflammatory and immune responses, such as the activation of CD4+ and Natural Killer T-cells. Ustekinumab binds with high affinity and specificity to the p40 protein shared as a common subunit by both IL-12 and IL-23. Through targeting the shared p40 component, Ustekinumab is able to block signalling by both interleukins. IL-12 and IL-23 eventually signal via master inflammatory system regulators tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB).
<DRUG_SUBUNIT="Heavy gamma-1 chain">
<DRUG_SUBUNIT NAME="Light kappa chain">
<DRUG_TARGET UNIPROT="P29460" TARGET_NAME="p40 subunit of IL-12 and IL-23">
The license holder for Ustekinumab is Johnson & Johnson. and the product website is

Saturday, 19 September 2009

New Drug Approvals - Pt. XVII - Telavancin (Vibativ)

The latest new drug approval, on 11th September 2009 was Telavancin - which was approved for the treatment of adults with complicated skin and skin structure infections (cSSSI) caused by susceptible Gram-positive bacteria, including Staphylococcus aureus, both methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) strains. Telavancin is also active against Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus) and Enterococcus faecalis (vancomycin susceptible isolates only). Telavancin is a semisynthetic derivative of Vancomycin. Vancomycin itself is a natural product drug, isolated originally from soil samples in Borneo, and is produced by controlled fermentation of Amycolatopsis orientalis - a member of the Actinobacteria.

Telavancin has a dual mechanism of action, firstly it inhibits bacterial cell wall synthesis by interfering with the polymerization and cross-linking of peptidoglycan - the mesh like outer membrane of the bacteria. It achieves this effect in a similar manner to the mechanism of Vancomycin. Vancomycin (and Telavancin) prevent the incorporation of NAM (N-acetylmuramic acid) and NAG (N-acetylglucosamine) subunits into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls. Secondly, Telavancin binds to the bacterial membrane and disrupts membrane barrier function.

Telavancin is a lipoglycopeptide antibiotic, and is semisythetic, being a derivative of the natural product Vancomycin, it has a molecular weight of 1755.6g.mol-1, as would be expected from a compound of this size, it comprehensively fails all the components of the Rule-of-Five. Telavancin is lipophillic and as expected, is not highly soluble in water. Following injection, Telavancin has a volume of distribution of 145mL/kg, a plasma half-life of 8hr and a clearance of 13.9mL/hr/kg.

Telavancin is available in the form of a reconstitutable powder for injection. Recommended dosage and full prescribing information can be found here. A course of treatment usually last seven or fourteen days and is a once daily dose of 10mg/kg (given as an hour long infusion). For a 'typical' adult of mass 70kg, this is a once daily dose of 700mg, this equates to a relatively large molar dosage (ca. 400umol).

Telavancin has a boxed warning.

Televancin has a complicated tricyclic structure, there are seven amino-acids as the core of the structure (the 'peptide' part of the lipoglycopeptide name), there are two sugar rings (the 'glyco' part of the name), and then, on the right hand part of the image above, a long lipophillic chain (the 'lipo' part of the lipoglycopeptide name). The biosynthesis of the parent natural product is fascinating, and is covered here. The specific differences of Telavancin compared to Vancomycin are the addition of the lipophillic alkyl chain, and the addition of the phosphate group (in the bottom right of the image). The glycopeptide antibiotic class of drugs include other Vancomycin derivatives, for example, Teicoplanin (launched as Targocid), Oritavancin (phase III trials), Dalbavancin (phase III trials) and the more chemically dissimilar Ramoplanin (phase III trials).

<NAME="Telavancin" >
64(98)39-16-19-51(116-53)45(81)26-39/h15-20,25-30,36-37,47-48,55,57,59-65,67-68,70-71,79,84-87,94-96,98-103H,7-14,21-24,31-35H2,16H3,(H2,83,97)(H,88,108)(H,89,105)(H,90,107)(H,91,109)(H,92,104)(H,93,106)(H,110,111)(H2,112,113,114)/t37-,47+,48-,55+,57-,59+,60+,61-,62+,63-,64+,65+,67+,68-,70+,71+,79-,80-/m0/s1" >
<ChemDraw=Telavancin.cdx >

The license holder is Theravance and is the product website.

Thursday, 17 September 2009

EU Innovative Medicines Initiative (IMI) 2nd call

The European Commission and EFPIA (European Federation of Pharmaceutical Industries and Associations) has recently announced the 2nd round of the Innovative Medicines Initiative (IMI) scheme, the amount of funding available is quite substantial, but arguably more important to the research community is the embracing of open data and services, and in particular coordinated pre-competitive activities (there is a lovely recent paper on these sort of activities here, a subscription may be required)
%J Nature Rev. Drug Discov. 
%D 2009
%P 701-708
%T Lowering industry firewalls: pre-competitive informatics initiatives in drug discovery
%A Barnes MR
%A Harland L
%A Foord SM
%A Hall MD
%A Dix I
%A Thomas S
%A Williams-Jones BI
%A Brouwer CR

To quote from the EU Commissioner of Science and Research, Janez Potocnik.

"We should see results from this exciting new research mechanism very soon and [...] new innovative medicines should reach European patients faster"

To quote from Bill and Ted

"Most excellent!"

The website for IMI is, and details of the second call are here

Sunday, 13 September 2009

Kinase SARfari is now live

Kinase SARfari is now live and online - free and open to one and all. We'll keep an eye on machine logs for the next couple of weeks, and so we may bounce it now and then. Please let us know if you have any issues with using it, and please tell us OS and browser versions for any bug reports.

The URL for kinase SARfari is

Full source code is also available, licensed under a very permissive Creative Commons licence. Mail us if you want this, but as soon as we sort out our downloads area, it will also be available from there.

The data in the backend database is in the process of being updated to a more recent data cut, and when this is done, we'll post details. We're also resurrecting the rhodopsin-like GPCR version. There is also an email address for sarfari support issues.

Sunday, 6 September 2009

Papers: Drug Target Central

Here is a paper (subscription required). It is written by Lee Harland (Pfizer Regenerative Medicine) and Anna Gaulton (ex Pfizer, but now in the ChEMBL group at the EMBL-EBI). It is an overview of Drug Targets, and some of the general principles of 'druggability' and ways to assess target tractability for drug discovery. In particular, the challenges of data integration are discussed.

%A L. Harland 
%A A. Gaulton
%T Drug Target Central
%J Expert Opin. Drug. Disc.
%V 4
%P 857-872
%D 2009