Allosterism: A Diatribe

So just what is an allosteric kinase inhibitor?

Imatinib / Gleevec / STI-571

well?

Masitinib

aka: Masivet, Kinavet & AB-1010 quietly joined the Phase iii club when it went Ph3 back in December.

WO/2008/98949

The History of Gleevec

chemistry @ 22:30

It’d be great if someone were to crystallize the first hit with Abl or Kit and compare this with 1IEP.  I suspect this would put the paradigm of structure based design in perspective.

Re-Engineering Gleevec

Alex Fernandez thinks he has a dehydron in action with Gleevec & c-Kit:

The interest of this goes way beyond this particular drug and this particular side effect. The idea is we could demonstrate for the first time that you can take a drug with side effects and re-engineer it to curb those side effects, Fernandez said in a telephone interview. (Reuters)

Adding a methyl group alpha to the the pyridine will make the activity of most kinases go away given a steric clash with the neighboring carbonyl. It’s interesting that the c-Kit activity stays behind, but the evidence given for the dehydron effect is through molecular dynamics and while as a rule I’ll try not to hold that against them, I don’t believe that the authors give a satisfactory answer as to why this new methyl group does not negate the compounds c-Kit activity through a simple steric interaction.

J Clin Invest 2007, 117, 4044
related: Cancer Res. 2007, 67 (9): 4028-33

Nippon Shanyaku took the alternate tack of making the core pharmacophore more potent and made it hit other things… In the discovery of the ph1 compound NS-187 (Inno-406):

Read all about it in the ’06 BMCL, the ’07 BMCL, the 2E2B, or through an Open Access offering here.

Tasigna Approved

aka nilotinib, AMN-107 is a Novartis‘ follow-on to Gleevec now approved for CML.

wiki; clinic; WO/2002/022597

Don’t abuse inventorship: Scientist

So a guy named Brian Druker wrote this piece on how Gleevec is overpriced, eh? Who is he? Well he appears to have written his own byline in case you hadn’t heard:

THE?

A quick googlification suggests he has plenty of nice things to say about Brian Druker and his role in Gleevec’s discovery… To his credit he does list Jürg Zimmermann (the named inventor on a series of patents starting with EP564409) as one of the ‘unsung heroes‘ in a history of Gleevec essay.

According to Zimmermann the discovery went something like this:

etc.

ht: spicy ip, via pharmalot

A Gleevec Cartoon?

Bangup Job

Tasigna

aka nilotinib, AMN-107 is a Novartis’ follow-on to Gleevec.

wiki; clinic; WO/2002/022597

WO2006101783

Hi Novartis, nice follow on with WO2006101783. Here’s a representative example and their Markush:

 

 

�Their latest application is a gleevec analog with a pyrrolopyrimidine hinge interaction, which looks nice enough. I wager they’re looking at a potency / selectivity angle. The added imidazo group probably brings in something like TIE2, or IKK… Think they could be a little more vague in your claims though?

 

>> Update. Ok, ok I guess there is more too it. I didn’t notice on the first pass but they claim to hit some Gleevec resistant strains. Good show.