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New Drug Approvals - Pt. XXII - Romidepsin (Istodax)
Approved on November 5th 2009 was Romidepsin (trade name Istodax). Romidepsin, previously known by the research codes FK-228, FR-901228 and NSC-630176, is a histone deacetylase (HDAC) inhibitor indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. CTCL is a slow-growing cancer of infection-fighting white blood cells called T-lymphocytes. Romidepsin binds directly to the HDAC active site blocking substrate access. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. Romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of cancer cells. Romidepsin is the fourth drug to be approved for CTCL, after Vorinostat (trade name Zolinza), Bexarotene (trade name Targretin) and Denileukin Difitox (trade name Ontak). Vorinostat is a small-molecule drug which also inhibits HDACs, whereas Bexarotene is a small-molecule retinoid selective for retinoid X receptors and Denileukin Difitox is an engineered protein combining interleukin-2 and diphtheria toxin, which binds to interleukin-2 receptors and introduce the diphtheria toxin into cells that express those receptors, killing the cells. Romidepsin is a Natural Product drug discovered from a fermentation broth of the bacteria Chromobacterium violaceum. It is a cyclic peptide with a molecular weight of 540.71 g.mol-1. It is highly protein bound in plasma (92% to 94%), with alpha1-acid-glycoprotein being the principal binding protein. Romidepsin undergoes extensive metabolism primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6 and CYP2C19. It has a terminal half-life of ~3 hours. Among one of the potential adverse events is the propensity for the compound to increase QT interval. The recommended dose of Romidepsin is 14 mg.m-2 administrated intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. The full prescribing information can be found here.
Romidepsin's chemical structure is (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone. It is a cyclic depsipeptide (peptide in which one or more amide bonds are replaced by ester bonds) with four component amino acids and a beta-hydroxyamide moiety (an amide and an hydroxy functional groups separated by two carbons atoms), which collectively form a 16-membered lactone with a disulfide bridge. The disulfide bond is reduced in the cellular environment, releasing the free thiol analogue as the active species.
<NAME="Romidepsin"> <SMILES="CC=C1C(=O)NC(C(=O)OC2CC(=O)NC(C(=O)NC(CSSCCC=C2)C(=O)N1)C(C)C)C(C)C"> <InChI="InChI=1S/C24H36N4O6S2/c1-6-16-21(30)28-20(14(4)5)24(33)34-15-9-7-8-10-35- 36-12-17(22(31)25-16)26-23(32)19(13(2)3)27-18(29)11-15/h6-7,9,13-15,17,19-20H,8,10- 12H2,1-5H3,(H,25,31)(H,26,32)(H,27,29)(H,28,30)/b9-7+,16-6-/t15-,17-,19-,20+/m1/s1"> <InChIKey="OHRURASPPZQGQM-GCCNXGTGSA-N"> <ChemDraw=Romidepsin.cdx>
The manufacturer of Romidepsin is Gloucester Pharmaceuticals, Inc. and the product website is www.istodax.com. -
FAQ: Is it safe to search with secret chemical structures over the web?
The short answer is maybe. It depends on your corporations/organisations confidentiality policies, whether you have spyware on your computer, whether someone is recording your network traffic, etc. We (the EMBL-EBI) will do nothing to store, analyse, disclose or otherwise publish any chemical structure queries, but fundamentally the searches are performed over the internet with the http protocol (as opposed to the encrypted https protocol).
We are investigating the implementation of a secure server currently (November 2009).
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FAQ: Is there a license agreement I need to sign for chembl?
There is no need to sign a license agreement for any of the chembl data or applications. Nor is there the requirement for any payment. The data/software is covered by a creative commons licence - Creative Commons Attribution-Share Alike 3.0 Unported License. If you have any detailed questions about licensing please get in contact with us.
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Conference: TACBAC 2010 - an update
A brief update of the forthcoming TACBAC 2010 conference. The schedule is now online and it looks very, very good (conflict of interest - I am motivated to say that). But really it does! Have a look for yourself if you don't believe me.
The picture above is the top hit for "TACBAC" in google images. TACtical BACon.
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FAQ: Where can I download StARlite?
Bad news and Good news: You cannot download StARlite. StARlite was a registered trademark for a database developed and marketed by Inpharmatica Ltd. Some of the databases and intellectual property of Inpharmatica Ltd. were licensed to the EMBL-EBI. What used to be known as StARlite is now part of chembl. chembl downloads accessible from here.
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Chembldb schema web meeting - 3pm GMT, 27th November 2009
Following unanticipated child illness last week, we will have a web-meeting walkthrough of the chembldb core schema on Friday 27th November at 3pm GMT. The excellent webhuddle will be used, so if you are interested it may be worth checking this out, setting up an account, checking it works on your machine, in advance of the meeting. Mail us if you want links to the phone number and webhuddle link.
We are aware that the 27th is over the forthcoming Thanksgiving weekend for our friends located in the United States of America, but we will do a further web-meeting the following week, for those unable to make it on the 27th.
Please, please, please use the above link, it is just too complex (for me) to manage emails with all sorts of titles, content and so forth! Also, it causes confusion (for me) if you forward the access details, and then I get messages, phone calls, smoke signals, etc. about the meeting if we need to change things.
I have just joined Google wave, and have a few invitations left if anyone is interested in getting one.
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Chembldb interface question
We have received a couple of questions about the 'privacy' of chemical structure searching of our chembldb interface. The root of these questions seems to be 'Is it safe for me to search with a proprietary structure?'. There are probably two components to this - privacy over the route to our servers, and the privacy of the query once it gets on to our site. Basically, we're not interested in what you are searching for, we don't store the queries at all, and have no desire to disclose this sort of data to anyone; however, there are a number of things we could do in the short-term to address some potential corporate/IP concerns.
We would also welcome contact/discussion to help us develop our longer term 'privacy' strategy for chembldb.
The image is from the excellent xkcd..... -
EBI Interfaces blog
There are only two issues with website implementation - 'interface' and 'content'. We have a project here at the EMBL-EBI connected with interface and UI principles, and they have a blog, here is a link to that blog.
