• INNS for kinase inhibitors - January 2011



    There are two new kinase inhibitor INNs in the latest WHO list of proposed INNs. (There are other kinase inhibitors in this document, but there are not new INNs/USANs - but if anyone knows anything about pacritinib I'd be glad to hear).



    Alisertib a.k.a. MLN-8237 - Millenium's Aurora kinase inhibitor, InChI key: APEDHRWNPCHTHU-UHFFFAOYSA-N InChI: InChI=1S/C27H19ClFN4O4/c1-36-21-5-3-4-20(29)23(21)25-19-10-15(28)6-8-17(19)24-14(12-30-25)13-31-27(33-24)32-16-7-9-18(26(34)35)22(11-16)37-2/h3-11,13H,12H2,1-2H3,(H,34,35) Phase 2



    Cenisertib a.k.a. AS-703569 and R-763 - Merck Serono's Aurora kinase inhibitor, InChI key: KSOVGRCOLZZTPF-QMKUDKLTSA-N InChI=1S/C24H30FN7O/c1-14-11-17(5-6-19(14)32-9-7-31(2)8-10-32)28-24-27-13-18(25)23(30-24)29-21-16-4-3-15(12-16)20(21)22(26)33/h3-6,11,13,15-16,20-21H,7-10,12H2,1-2H3,(H2,26,33)(H2,27,28,29,30)/t15-,16+,20+,21-/m1/s1 Phase 1

  • Todays Found Natural Product: 2: Solanine


    We know that man (and women) can actually live on potatoes alone, but there is a lurking danger in the humble spud, and due to poor housekeeping on my part, I managed to transform man's starchy friend into a toxic time-bomb - enough of the dramatics, I left some potatoes in the daylight on top of my microwave and they went green. And as all children are taught from an early age, green potatoes are 'poisonous'. This toxic effect is mediated by a number of compounds, but the major one is Solanine - the toxic effects include gastrointestinal, cardiac and neurological effects. Another toxic component of potatoes is the closely related compound Chaconine, and tomatos contain yet another related toxic compound Tomatine. Doses of 3 to 6 mg per kg of Solanine can be fatal to a human (so for an average 70 kg human, 210-420 mg of Solanine). A 'green potato' can have up to 1000 mg of Solanine per kg, so it is relatively easy to ingest enough potato to elicit a toxic response.

    The chemistry and biology behind this is quite interesting, and basically it is a defence mechanism against fungi, insects, slugs, and other potato predators, and this includes us - since we are now the super-predator for the potato species (Solanum tuberosum). The exposed portions (stems, leaves, berries, etc) of the potato plant have high levels of Solanine - in fact potatoe plants are in the same family as the Deadly Nightshade (Atropa belladonna) of North European folklore (itself a cornucopia of useful and toxic natural products). Normally the tubers of potato plants are buried, hidden from light, and have low levels of Solanine. When harvested they are typically kept in light proof sacks, or in the dark of a larder. When exposed to light, the potato responds by kicking off photosynthesis (and inducing chlorophyll production to achieve this, this is the green colour in the skin). Solanine is not green, but it's production tracks that of chlorophyll - therefore the green colour is a useful biomarker of potato toxicity.




    Solanine is a complex steroidal glycoalkaloid that can cause apoptosis in a broad range of cells (believed to be via a Bcl-2 apoptosis pathway, since solanine reduces the expression of Bcl-2 in HepG2 cells (an oft used human cell line for toxicity testing). Solanine has a broad range of pharmacology ranging from disrupting lipid membrane structure and stability, there is a strong affinity of Solanine for cholesterol (an essential membrane component) leading to cell lysis; Solanine also inhibits butyryl cholinesterase - and thereby affects neurotransmission. The chemical structure of Solanine contains a large fused-ring basic alkaloid, coupled to three sugar rings. These sugar rings will hydrolyse in the acid of the stomach, and so oral ingestion is less toxic than other delivery routes. Also Solanine is lipophilic and will therefore partition into fats (one more reason to enjoy chips!).

    Finally the potato genome is being determined, and so the biosynthetic genes for Solanine will be in there. The PlantCyc resource has a useful overview of the biosynthesis of Solanine - which is derived from the same precursor (mevalonic acid) used in the synthesis of cholesterol.  As you would expect due to the immense commercial importance of the potato, this field has attracted some patenting interest e.g. US 7439419.

  • 2011 EIPOD Fellowships with ChEMBL


    EMBL run a vibrant postdoctoral fellowship programme called EIPOD. This funds interdisciplinary projects between research groups within EMBL. The 2011 appointment process is just starting, and we are pleased to announce that the ChEMBL group is involved in two projects this year - both based around using informatics techniques to improve Drug Discovery. EIPOD projects have multiple supervisors, with one lab acting as the lead and primary host for the postdoc. Projects are either selected from an approved list, or the candidate can develop their own interdisciplinary project following consultation with the relevant group leaders.

    The first project is part of our interest in mining the Internet for clinical development candidate data, delivering an open resource for data-mining and also to lower barriers to data sharing and collaboration. This EIPOD addresses part of this broader project (a sort of ‘Open Source Competitive Intelligence Resource for Drug Discovery’), and specifically looks to identify, define and annotate newly disclosed/published clinical candidates from non-patent and non-literature sources. The project will be led by the text-mining and literature groups here at the EBI under Dietrich Rebholz-Schuhmann and Johanna McEntyre. Details of the project are here.

    The second project is connected with using next generation sequencing (NGS) techniques to profile the organisms present in natural product screening collections and environmentally derived samples. We will attempt to develop a series of heuristics and a combined experimental and informatics pipeline to identify ‘interesting’ samples. Interesting here means those likely to contain chemically novel natural products, with an aim to use these as a source of new leads for drug discovery. This project will be based in the ChEMBL group, and will involve collaboration with the Hunter (EBI) and Bork (Heidelberg) groups. Details of the project are here.

    Further details of the application process and deadlines can be found here, and if you are interested in discussing either of the projects (or would be interested in developing your own project idea involving the ChEMBL group), please feel free to mail us.

    There are also several other excellent Chemical Biology EIPOD projects available in other labs at EMBL.

  • New Drug Approvals 2011 - Pt. I Spinosad (NatrobaTM)








    partial ATC code: P03A

    The first FDA new drug approval of 2011 is Spinosad, approved on Jan 18th 2011 (NDA 022408). Spinosad (tradename: Natroba) is a pediculicide, indicated for the topical treatment of head lice (the parasitic insect Pediculus humanus capitis) infestations in patients aged over four years of. One gram of Natroba contains 9 mg of Spinosad as a viscous suspension.

    Spinosad has a unique mode of action that is different from all other known pediculicides. Spinosad causes excitation of the insect nervous system, leading to involuntary muscle contractions, prostration tremors and finally paralysis and death. These effects are similar to those associated with the activation of nicotinic acetylcholine receptors (nAChRs), and there is evidence that insect nAChRs are involved in the mechanism of action of spinosyn A and D (two active components of Spinosad) a representative nAChR for a target species is Drosophila melanogaster nAChR Dalpha6 (UniProt:Q86MN8).  nAChRs are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction. These receptors are triggered by the binding of the neurotransmitter acetylcholine and their stimulation causes muscular contraction. This protein family is structurally related to the significant family of human drug targets - the ligand-gated ion channels, in which drugs bind at extracellular sites in the so-called ligand-binding domain (Pfam:PF02931).

    Spinosad has already been used for a number of years as an oral anti-flea medication for pets and also to control a variety of insect pests, such as fruit flies, caterpillars, spider mites, fire ants; and has now received approval as a prescription human medication. Since it does not significantly affect beneficial insects and predatory mites, Spinosad is actually recommended for use in an integrated pest management program for commercial greenhouses. Spinosad is the first head lice treatment that does not require combing and it has been shown to be more effective in eliminating head lice than previously approved treatments. These include both natural and synthetic products, such as Malathion 0.5% (tradename: Ovide), Permethrin 1% (tradename: Nix), Pyrethrins (tradename: Rid) and the recently approved Benzyl Alcohol 5% (tradename: Ulesfia; approved in 2009). 

    Spinosad, the active ingredient, is derived from the fermentation of a naturally occurring soil dwelling bacterium called Saccharopolyspora spinosa, a rare actinomycete collected on a Caribean island in 1982. Spinosad is a mixture of the natural products spinosyn A and spinosyn D in a ratio of approximately 5 to 1.

    Spinosyn A (IUPAC: (2R,3aS,5aR,5bS,9S,13S,14R,16aS,16bR)-13-{[(2R,5S,6R)-5- (dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-methyl-7,15-dioxo-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-d]oxacyclododecin-2-yl 6-deoxy-2,3,4-tri-O-methyl-α-L-mannopyranoside; INCHIKEY: SRJQTHAZUNRMPR-UYQKXTDMBW; SMILES: [H][C@@]12C[C@H](C[C@@]1([H])[C@]1([H])C=C3C(=O)[C@H](C)[C@H](CCC[C@H](CC)OC(=O)C[C@@]3([H])[C@]1([H])C=C2)O[C@H]1CC[C@@H]([C@@H](C)O1)N(C)C)O[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC; ChEMBL: CHEMBL501411; ChEBI: CHEBI:9230; PubChem: CID115003; ChemSpider: 391358) has a molecular weight of 731.96 Da, no hydrogen bond donors, eleven hydrogen bond acceptors, a calculated logP of 4.9 and a polar surface area of 111 Å2. Spinosyn D differs from Spinosyn A, having one more methyl group at the double bond carbon of the cyclohexene of the indacene derived central moiety. Thus, Spinosyn D (IUPAC: (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-{[(2R,5S,6R)-5-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-4,14-dimethyl-7,15-dioxo-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-d]oxacyclododecin-2-yl 6-deoxy-2,3,4-tri-O-methyl-α-L-mannopyranoside; INCHIKEY: RDECBWLKMPEKPM-PSCJHHPTBK; SMILES: [H][C@@]12C[C@H](C[C@@]1([H])[C@]1([H])C=C3C(=O)[C@H](C)[C@H](CCC[C@H](CC)OC(=O)C[C@@]3([H])[C@]1([H])C=C2C)O[C@H]1CC[C@@H]([C@@H](C)O1)N(C)C)O[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC; ChEMBL: CHEMBL503450; ChEBI: CHEBI:9232; PubChem: CID183094; ChemSpider: 159214) has a molecular weight of 745.98 Da, and, like Spinosyn A, has no hydrogen bond donors, eleven hydrogen bond acceptors, a calculated logP of 4.8 and a polar surface area of 111 Å2. Both Spinosyn A and B fail the rule of five. A notable feature of both spinosyn structures is the tertiary amine, which will be protonated under physiological conditions and the relatively small macrolide (in this case a 12-membered cyclic lactone) ring fused to the rigid and lipophilic 5:6:5 ring system. Many natural products contain a macrolide ring.

     
    The full US prescribing information can be found here. The license holder is ParaPRO LLC and the product website is www.natroba.com.

  • January 2011 USANs



    The January 2011 USANs have been published, these are:

    USANResearch code StructureDrug Type Drug ClassTarget
    insulin-degludecNN-1250Insulin degludec nn-1250 GIVEQCCTSICSLYQLENYCN FVNQHLCGSHLVEALYLVCGERGFFYTPKproteintherapeuticinsulin receptor
    lesinuradRDEA-594Lesinurad RDEA-594 FGQFOYHRJSUHMR-UHFFFAOYSA-Nsynthetic small moleculetherapeuticURAT1 transporter
    vidupiprantAMG-853AMG-853 Vidupiprant PFWVGKROPKKEDW-UHFFFAOYSA-Nsynthetic small moleculetherapeuticCRTH2 receptor and D-prostanoid receptor


    Drug TypeNumber
    synthetic small molecule2
    natural product derived small molecule0
    protein1
    monoclonal antibody0
    enzyme0
    Total for year3



  • The ChEMBL library



    I rediscovered a cool app for the Mac recently - Delicious Library 2, and following some of our books going 'missing', I'm adding my book collection to a on-line library. At the moment, I've done most of the computing books.

  • ChEMBL Schema Walkthrough Webinar - 27th January 2011


    We'll be running a ChEMBL database schema walkthrough at 3pm GMT on Thursday 27th January.

    There will be some changes to the existing schema in the forthcoming ChEMBL_09 release, to allow us to incorporate a lot more information about approved drugs. Therefore this webinar may be of interest not just to new users, wishing to understand the schema/data model, but also existing users who want more information about the changes.

    We will use webhuddle for the meeting. You don't need an account or any software, just a Java enabled web-browser. There will also be a separate number to dial into the audio.

    Please click here to sign up for meeting details.

  • ChEMBL (and other EMBL-EBI resources) are now back online

    Following planned downtime, the ChEMBL database, and other ChEMBL resources are now back online.