Whats that doin there?

Looks like Merck’s released an allosteric CHK1 pdb: 3F9N

3F9N

AZD-7762

It’s going ph1, it’s from WO/2005/066163, and it’s been described.

Somebody send it to Ambit.  XL-844,  PF-477736, IC-83 are the known competition.

PDB Update

Merck (WP) Chk1, 2R0U: BMCL

PF-477736

PF-477736 is Pfizers phase 1 Chk1 inhibitor being given in combination with Gemcitabine. They haven’t confirmed the structure yet, but…

It just so happens that 2007/113671 covers the above Chk1 inhibitor in combination with chemotherapy.   It may be the wrong structure, but till proven thus, it’s on the list.  Click for selectivity.

PDB Update

>> Update >> Biochemistry article on the Plk1 structure.

Woohoo! First published kinase domain Plk1 structures from Pfizer:

2OWB Plk1 w/ pyrrolopyrazole inhibitor
2OU7 Plk1 w/ ANP

and a Chk1 structure from Merck: 2HOG; BMCL

PDB Update

2NP8: Aurora Kinase. Novartis has a series of these kinds of compounds described in: JACS ’06 – 2182, but its looking like this came out of Takeda, and the companion article to this xray is in the ‘to be published’ category. Only other Aurora relevant Xray is a mutant: 2C6E, and of course the Abl mutant with VX680: 2F4J.

Interesting, looks that there’s a lysine residue on the glycine rich loop which is fairly specific to Aurora and appears to hydrogen bond the trifluromethyl group. Else these look to be in a similar conformation to the Rigel pyrimidines.

Also new today: 2FGA; Chk1 Apo: Bioorg Med Chem Lett ’06 – 2293 Peculiar, this is a low resolution apo with identity to the much earlier high resolution Chk1 apo: 1IA8.

WO2006135604

WO2006135604 is a recent Chk1 offering via Merck.

WO2006106326

A big wuzzup to my peeps representin in the big 48,

Umm, thats country code 48. Umm, well you see I mean, ahh nevermind. Hi AstraZeneca nice CHK1, PDK1 AND PAK inhibitors. KP won’t lie, he hasnt seen a whole lot of PAK or PDK1 inhibitors, but he’s sure they’ve been implicated in everything from breast cancer to the tooth fairy. Chk1 PDK1 have been around the virtual-block for a while now, and there’s quite a few Xray’s in the PDB. Nothing quite like what you’re up to here though, so I’m quite happy to be poking through your latest application:

I don’t have a real good guess on how it’s binding, if pressed I’d say the amide is likely hitting the hinge, the aryl is headed off into H1, and the piperidines are in the ribose region (Chk1 acid residue in white below, is also in PDK1).

->> mid-post update, I wasn’t very clear on the binding mode until I cracked open PDK1 bound to staurosporine (1OKY) and overlayed it. I’d say I’m a little more confident now:

It strikes me that I’ve seen the indole-carboxamide as a kinase active scaffold before – something in the IKK vein. I’ll have to look it up and update tomorrow. Nice app.

Hej då

>> update >> indeed WO2006034317 is a Glaxo UK, IKK application from March, 06. which itself appears to be a continuation of SKB WO2005067923.   

 

WO20060105865

Hello there Merck KGaA,

Nice Chk1 application. This one’s a modification of a previous GSK application WO2006072354 [Thats glycogen synthase kinase, not glaxo (I know, kinasepro wishes one of them would change their name too)]

This functional group is not without precedent, occuring in BMY25368 a histamine H2-receptor antagonist and elsewhere in the medicinal chemistry patentscape. Notably Schering and Wyeth seem to be all over the functional group for the last 25 years. Not so much in Kinases, but somebody in Pearl River must like them because American Cyanimide, American Home Products, and Wyeth have all messed around with them quite a bit through their history. They describe them as alpha-amino acid isosteres: J. Med. Chem. 1998, 236.

I guess KP shouldn’t be surprised to find the group has been used before for kinase inhibitors. It doesn’t seem like anyone has taken them very far, but OSI has a series of derivatives that hit c-Kit WO2006034111, and Abbott tried to use them as a urea mimic in a series of PP1 analogs: US20040014756.

O=C(C(NC3=CC(C(NC(CN5CCOCC5)=O)=NN4)=C4C=C3)=C1N[C@H](C)C2=CC=CC(O)=C2)C1=O