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5.00613

Sigma-Aldrich

p21-Activated Kinase Inhibitor II, PF-3758309

Synonym(s):

p21-Activated Kinase Inhibitor II, PF-3758309, PAK Inhibitor II, PF3758309, ( S)-N-(2-(Dimethylamino)-1-phenylethyl)-6,6-dimethyl-3-(2-methylthieno[3,2-d]pyrimidin-4-ylamino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, PAK Inhibitor II, PF3758309, (S)-N-(2-(Dimethylamino)-1-phenylethyl)-6,6-dimethyl-3-(2-methylthieno[3,2-d]pyrimidin-4-ylamino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide

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About This Item

Empirical Formula (Hill Notation):
C25H30N8OS
CAS Number:
Molecular Weight:
490.62
UNSPSC Code:
12352200
Pricing and availability is not currently available.

Assay

≥99% (HPLC)

Quality Level

form

powder

manufacturer/tradename

Calbiochem®

storage condition

OK to freeze
protect from light

color

yellow-white

solubility

DMSO: 100 mg/mL

storage temp.

−20°C

InChI

1S/C25H30N8OS/c1-15-26-18-11-12-35-20(18)23(27-15)29-22-17-13-33(25(2,3)21(17)30-31-22)24(34)28-19(14-32(4)5)16-9-7-6-8-10-16/h6-12,19H,13-14H2,1-5H3,(H,28,34)(H2,26,27,29,30,31)/t19-/m1/s1

InChI key

AYCPARAPKDAOEN-LJQANCHMSA-N

General description

A cell-permeable pyrrolopyrazole that acts as a potent inhibitor against p21-activated kinases (Ki in nM/[ATP] in µM = 13.7/200, 18.7/40, 18.1/80. 17.1/72, respectively, in PAK1, PAK4, PAK5, PAK6 in vitro kinase assays; IC50 = 190 and 99 nM against PAK1 and PAK3, respectively) and potently inhibits cellular PAK4-mediated GEF-H1 Ser810 phosphoryation (IC50 = 1.3 nM using HEK293-derived TR-293-KDG cells) by directly targeting the kinase ATP-binding site in a reversible manner (Kd = 4.5 nM; koff = 0.010/s; t1/2 = 68 s; by SPR using rhPAK4300-591 kinase domain). PF-3758309 is expected to inhibit cellular AMPK and RSK2 activity only at much higher concentrations (estimated IC50 = 40 nM and 171 nM, respectively, assuming cellular [ATP] = 2 mM) and exhibit even less potency toward 144 other cellular kinases when administered at effective concentration range for cellular PAK1/4/5/6 inhibition. In addition to inhibiting PAK4-dependent cellular signaling (IC50 = 24.2 nM against 20 ng/mL TNFα-stimulated NF-κB reporter transcription in HEK293T) and proliferation (IC50 = 0.24 and 27 nM, respectively, against HCT116 and A549 colonies formation) in cultures in vitro, PF-3758309 is also reported to effectively inhibit human tumor growth in nude mice in vivo (% inhibition/tumor/BID p.o. dosage in mg/kg = 97%/HCT116/20, 106%/Colo205/20, 89%/MDA-MB231/20, 71%/A549/10, 85%/M24met/25).
A cell-permeable pyrrolopyrazole that acts as a potent inhibitor against p21-activated kinases (Ki in nM/[ATP] in µM = 13.7/200, 18.7/40, 18.1/80. 17.1/72, respectively, in PAK1, PAK4, PAK5, PAK6 kinase assays; IC50 = 190 and 99 nM against PAK1 and PAK3, respectively) by directly targeting the kinase ATP-binding site in a reversible manner (Kd = 4.5 nM using rhPAK4300-591 kinase domain). Inhibits PAK4-dependent cellular signaling (IC50 = 24.2 nM against TNFα-stimulated NF-κB activity in HEK293T) and proliferation (IC50 = 0.24 and 27 nM, respectively, against HCT116 and A549 colonies formation) in vitro and the growth of human tumors in nude mice in vivo (10 to 25 mg/kg; b.i.d. p.o).

Please note that the molecular weight for this compound is batch-specific due to variable water content. Please refer to the vial label or the certificate of analysis for the batch-specific molecular weight. The molecular weight provided represents the baseline molecular weight without water.

Biochem/physiol Actions

Cell permeable: yes
Primary Target
PAK
Reversible: yes
Target IC50: 190 and 99 nM for PAK1 and PAK3, respectively)

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

Following reconstitution, aliquot and freeze (-70°C). Stock solutions are stable for up to 6 months at -70°C.
Use only fresh DMSO for reconsitution.

Other Notes

Murray, B.W., et al. 2010. Proc. Natl. Acad. Sci. USA.107, 9446.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Storage Class Code

11 - Combustible Solids

WGK

WGK 3

Flash Point(F)

Not applicable

Flash Point(C)

Not applicable


Certificates of Analysis (COA)

Search for Certificates of Analysis (COA) by entering the products Lot/Batch Number. Lot and Batch Numbers can be found on a product’s label following the words ‘Lot’ or ‘Batch’.

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