KinasePro: Done

Thank you for taking part in this just-over-a-year-long experiment known affectionately industry-wide as: KinasePro. Its been a fun ride, and through the 504 posts, 840 comments, and 400,000 page-views I’ve learned a great deal from all of you.

In addition to KinasePro I have a handful of other medicinal chemistry related projects in the works, but frankly keeping this site updated is just getting in the way of getting them done. These endeavors will hit the world-stage in the coming year, so send me an email if you’d like to be updated as they comes of age.

So long, and thanks for all the fish.

R-343

Rigel gets 5M & some good news from Pfizer:

…Pfizer (NYSE: PFE), has begun a Phase 1 clinical trial of an inhaled formulation of Rigel’s small molecule syk kinase inhibitor, R343, for the treatment of allergic asthma…

TG-101348

Targegen’s got a press release:

Plans to initiate a multi-center clinical trial of TG101348, an internally discovered, oral, potent, and highly selective JAK2 inhibitor in January, 2008

A poster at ASH:

…Dual-Acting JAK2/FLT3 Small Molecule Kinase Inhibitor for the Treatment of AML

and some pyrimidines in WO/2007/053452:

PDB Update

Berkeley’s got a Nature 2007, 450, 741 on a peptide that inhibits EGF 

and the PDB’s released yesterday: 2RFD 3.6 Å, 2RF9 3.5 Å, 2RFE 2.9 Å

To understand what they’re talking about I had to read the earlier piece in Cell.   You could probably just skip it because the Monkey Wrench breaks it down for you.

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.

SGX-523

SGX just submitted an IND for their selective C-Met inhibitor SGX-523

recent webcast here

Piper Jaffray

…It’s an investor dog and pony show, and it was last week. Who was there?

Exelixis: George Scangos had this to say on Kinase selectivity:

We get a lot of questions about whether we think that less specific multi-targeted kinase inhibitors are better then more specific kinase inhibitors. I think there is no general answer to that question. Personal view is when your working on the outside of the cell inhibiting a single molecule leads to efficacy, but the efficacy is limited and you can greatly increase the potency by hitting multiple targets at the same time without increasing the toxicity significantly, and I think there is plenty of clinical data now to show that that’s true.

On the other hand when your working downstream inside the cell in the biochemical pathway I think its important to be very specific and so we have a number of other compounds that work downstream within those pathways that are very specific so we tailor the compounds to what we think will optimize balance between efficacy and safety. We have some multi-targeted inhibitors we have some highly selective inhibitors, and we have some that hit a couple of targets.

They keep taunting us with bubble images of XL-880 and XL-184, So here have a guess:

There was also a bit on you should buy XL-647: its ‘More potent’, ‘More safe’ & ‘hits the T790M mutation’

Incyte: /Flexed on the impressive JAK inhibitor results they expect to tell you all about at ASH and beyond.

OSI: Now profitable with Tarceva, whose main competition interestingly enough is Alimta. It sounds like they are keeping OSI-906 for now, but OSI-930 and OSI-632 seem to be for sale.

Infinity: was there dropping some knowledge on the chaperoneness of HSP90 as it relates to kinase inhibitors and resistance.