Plethora ‘o’ PDB’s

GSK’s AKT stuff: 3d0e, 3E8D, 3E87, 3E88; J Med Chem, KP

SGX: Jak2 3E64, 3E63, 3E62, BMCL

Shokat: SRC, SRC, SRC, SRC, PI3K-Gamma, PI3K-Gamma

reminds me of OSI-906 or vice versa

Astrazeneca: CDK2 BMCL: 2W05

Amgen: P38 J Med Chem; 3DT1

LCK: 2ZM4, 2ZM1

Astex: An Oral Candidate for CDK2

Astex’s fragment based discovery effort yielded an oral candidate back in ’05, and now with WO/2007/129066 & WO/2007/129062 the world can have a look. It’s probably AT-9311 even though I could’a swore I heard’m say that their Novartis’ partnered material was of a different series then AT-7519. Perhaps its 7519 I have wrong…

pM CDK2

0.22 uM GSK3b

Mouse: 40-50%F (DMSO/Water/PEG 1/2/7)

PDB Update

c-Met + Indolinone: 2RFS; Amgen
c-Met + pyrimidone: 2RFN; Amgen <- Clearly the highlight of the day, but no image from me yet. I’m looking at it wondering where did all the polar contacts go? Peculiar structure, but noteworthy as the first published structure in the xl-880/kirin/bms/genentech/array/methylgene acyl urea isostere genre.

CDK2 + a pyrimidine macrocycle: 2J9M; chemmedchem; Schering AG

CK2: 2RKP: 1.56A

PKA: 2QCS

SGP’s CDK CIPs

‘Nother set of light reading galloping down the hill from Schering-Plough on CDK. 3 continuations: 20070072882, 20070072881, and from 20070072880:

Schering’s latest CDK stuff

Schering-Plough has a series of CDK inhibitors of which the latest installment is: US20070066621. Earlier app’s in this series appear as a combined effort via SP and PCOP, and Pharmacopeia has a press release suggesting that the collaboration has an oncology candidate in Ph1. Hrmph, No ph1 oncology trials via ScheringP in the US and the press on this stuff is a little thin.

Vernalis described related series’ in Bioorg Med Chem Lett ’05, 863; 1Y8Y 1Y91 and Bioorg Med Chem Lett ’06, 1353; 2C68, 2C69, 2C6T, 2C6O, 2C6M, 2C6L, 2C6K, 2C6I

SNS-032

‘nother Phase1 underway CDK2,7,9 formerly BMS-387032 for

patients with advanced B-cell malignancies

press release and an ‘old’ J Med Chem.

US20060241297

Hi again Cyclacel, Good idea to cover the pyridines too. Thanks for giving us the data. And hey, it appears you can walk around the activity wheel a little by varying the amine portion of the aminothiazole, but less then 10-fold over all the CDKs and GSK3 / Aurora? Unless your not showing us your ace, it makes Kinasepro wonder just how selective your PLK1 inhibitors are.

CC(N=C(NCCOC)S3)=C3C1=NC(NC2=CN=C(OC)C=C2)=NC=C1

US20060235065

Wie Gehts Roche Penzeburg?

This doesn’t otherwise strike Kinasepro as a very crowded chemical space, but it looks as though Roche is stepping a little close to Astex toes on this one… Looks as though Astex borrowed the general idea from Aventis, so hey thats just the way it goes I guess.

There’s a handful of PDB’s such as the 2C3K and 2C3L (CHK1) that suggest how these compounds bind to kinases.

US20060235025

How now Schering-Plough, Nice purvalanol analogs as CDK2 inhibitors.

Anything earthshaking here? Hmm… Not really, but look hard enough, and KP always learns something.

Yep, hadn’t noticed the bromide as an isopropyl isostere before, but this is a continuation from US2006041131, WO2004022559. Schering has been beating on this and other 6-5 purine isosteres for some time (WO2004026877). There’s been plenty of Biotech sniffing around here. Vernalis has a similar CDK series (WO2004087707), and a Bioorg. Med. Chem. Lett. 2005, 863 (appears they’ve dropped the series).  Ono has some c-Jun (WO2005035516) inhibitors on the scafford. So whats new here? Vernalis describes selectivity issues.  Maybe they cracked that nut, otherwise its not obvious to me.
BrC2=C1N(N=C2)C(NC3=CC=NC=C3)=CC(C4CCCNC4)=N1 BrC2=C1N(N=C2)C(NC3=CC=CN=C3)=CC(N4CCC[C@@H]4CO)=N1 CC(C)N2C=NC1=C(NC3=CC(Cl)=CC=C3)N=C(N[C@H]([C@H](C)C)CO)N=C12

US7122552

Hi Vertex,

Nice JAK3 / CDK2 application. Kinasepro notices that you folks patent an aweful lot of compounds, and chemotypes. Keeps me busy, but I have to wonder how you’ll find time to develop all these things.

There have been innumerable CDK2 inhibitors enumerated, and Xrays described. JAK3 - hmm… not so much. Interesting to me if you guys actually found a scaffold that hits’m both, because of some key residue differences. (gatekeeper: met vs. phe, and a selectivity residue: cys909 vs asn322)

Anyhow cool fused-pyrazoles, I guess if you squint a little you could find some similarities with the Aurora kinase inhibitor: VX680