PF-03758309
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MedKoo CAT#: 205581

CAS#: 898044-15-0 (free base)

Description: PF-3758309, also known as PF-03758309, is a PAK4 inhibitor, is also an orally bioavailable small-molecule inhibitor of p21-activated kinase 4 (PAK4) with potential antineoplastic activity. PAK4 inhibitor PF-03758309 binds to PAK4, inhibiting PAK4 activity and cancer cell growth. PAK4, a serine/threonine kinase belonging to the p21-activated kinase (PAK) family, is often upregulated in a variety of cancer cell types and plays an important role in cancer cell motility, proliferation, and survival.


Chemical Structure

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PF-03758309
CAS# 898044-15-0 (free base)

Theoretical Analysis

MedKoo Cat#: 205581
Name: PF-03758309
CAS#: 898044-15-0 (free base)
Chemical Formula: C25H30N8OS
Exact Mass: 490.22633
Molecular Weight: 490.62
Elemental Analysis: C, 61.20; H, 6.16; N, 22.84; O, 3.26; S, 6.54

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 750.0 Ready to ship
500.0mg USD 1650.0 Ready to ship
1.0g USD 2950.0 Ready to ship
2.0g USD 5250.0 Ready to ship
Bulk inquiry

Related CAS #: 898044-15-0 (free base); 1279034-84-2 (HCl).  

Synonym: PF-03758309; PF03758309; PF 03758309; PF-3758309; PF-3758309; PF3758309; PF 3758309.

IUPAC/Chemical Name: (S)-N-(2-(dimethylamino)-1-phenylethyl)-6,6-dimethyl-3-((2-methylthieno[3,2-d]pyrimidin-4-yl)amino)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide.

InChi Key: AYCPARAPKDAOEN-LJQANCHMSA-N

InChi Code: 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

SMILES Code: O=C(N(C1)C(C)(C)C2=C1C(NC3=C4C(C=CS4)=NC(C)=N3)=NN2)N[C@@H](C5=CC=CC=C5)CN(C)C

Appearance: white to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: PF-3758309 is a potent, reversible ATP-competitive inhibitor of PAK4 (Kd= 2.7 nM; Ki=18.7 nM) with IC50s of 190nM and 99nM for PAK2 and PAK3, respectively.
In vitro activity: In the present study, using high-throughput small-molecule inhibitor screening, it was attempted to evaluate the antitumor effect and molecular mechanism of PF-3758309 in human neuroblastoma. To evaluate the inhibitory effect of PF-3758309 (Fig. 2D) on neuroblastoma cells, 8 neuroblastoma cell lines were treated with the PAK4 inhibitor PF-3758309 (Fig. 2E). Pharmacological inhibition of PAK4 by PF-3758309 treatment resulted in significant inhibition of proliferation in neuroblastoma cells with high expression of PAK4, that is, KELLY, NBL-S, SH-SY5Y and IMR-32 cells. In contrast, cells with low levels of PAK4 expression were less sensitive to PF-3758309 exposure. PF-3758309 treatment was found to have a dose-dependent inhibitory effect on the growth of neuroblastoma cells (Fig. 2E). The IC50 value of PF-3758309 was determined in 4 neuroblastoma cell lines: SH-SY5Y, 5.461 µM; IMR-32, 2.214 µM; NBL-S, 14.02 µM; KELLY 1.846 µM. The cells that were affected by PF-3758309 presented with abnormal morphological features; most of the cells had shrunk and lost their ability to adhere, and they were observed to be floating (Fig. 2F). In addition, clone formation assay showed that PF-3758309 caused a reduction in the number of both SH-SY5Y and IMR32 cell clones (Fig. 3A and B). These results demonstrate that PF-3758309 effectively impairs the growth potential of neuroblastoma cells. Oncol Rep. 2017 Nov; 38(5): 2705–2716. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780023/
In vivo activity: The effects of p21 activated kinases (PAKs) on tumour immune response and gemcitabine response were examined in PDA. An orthotopic murine PDA model, in which pancreatic cancer cells were injected to the tail of pancreas, was used. The mice were treated with PAK inhibitor, PF‑3758309, plus or minus gemcitabine. Tumour growth was measured by volume and weight. In PAK1 WT mice, either PF-3758309 or gemcitabine alone significantly reduced tumour growth by decreasing the tumour volume (Fig. 6A and C) and tumour weight (Fig. 6B), compared to untreated controls. Either PF-3758309 or gemcitabine alone inhibited tumour growth by decreasing cell proliferation as measured by Ki67 immunohistochemistry (Fig. 7A). The proliferation in tumours from PAK1 WT mice treated with either PF-3758309 or gemcitabine was reduced to 60.6% and 60.1% of that in tumours from untreated mice. These results indicate that inhibition of PAKs by PF-3758309 or by PAK1 knockout sensitized pancreatic cancers to gemcitabine in vivo at least by decreasing cell proliferation. Int J Oncol. 2018 Jan;52(1):261-269. https://pubmed.ncbi.nlm.nih.gov/29115428/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 10.0 20.4

Preparing Stock Solutions

The following data is based on the product molecular weight 490.62 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Wang K, Huynh N, Wang X, Pajic M, Parkin A, Man J, Baldwin GS, Nikfarjam M, He H. PAK inhibition by PF-3758309 enhanced the sensitivity of multiple chemotherapeutic reagents in patient-derived pancreatic cancer cell lines. Am J Transl Res. 2019 Jun 15;11(6):3353-3364. PMID: 31312349; PMCID: PMC6614655. 2. Li Z, Li X, Xu L, Tao Y, Yang C, Chen X, Fang F, Wu Y, Ding X, Zhao H, Li M, Qian G, Xu Y, Ren J, Du W, Wang J, Lu J, Hu S, Pan J. Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22. PMID: 29048629; PMCID: PMC5780023. 3. Bradshaw-Pierce EL, Pitts TM, Tan AC, McPhillips K, West M, Gustafson DL, Halsey C, Nguyen L, Lee NV, Kan JL, Murray BW, Eckhardt SG. Tumor P-Glycoprotein Correlates with Efficacy of PF-3758309 in in vitro and in vivo Models of Colorectal Cancer. Front Pharmacol. 2013 Mar 22;4:22. doi: 10.3389/fphar.2013.00022. PMID: 23524533; PMCID: PMC3605511. 4. Wang K, Huynh N, Wang X, Baldwin G, Nikfarjam M, He H. Inhibition of p21 activated kinase enhances tumour immune response and sensitizes pancreatic cancer to gemcitabine. Int J Oncol. 2018 Jan;52(1):261-269. doi: 10.3892/ijo.2017.4193. Epub 2017 Nov 7. PMID: 29115428.
In vitro protocol: 1. Wang K, Huynh N, Wang X, Pajic M, Parkin A, Man J, Baldwin GS, Nikfarjam M, He H. PAK inhibition by PF-3758309 enhanced the sensitivity of multiple chemotherapeutic reagents in patient-derived pancreatic cancer cell lines. Am J Transl Res. 2019 Jun 15;11(6):3353-3364. PMID: 31312349; PMCID: PMC6614655. 2. Li Z, Li X, Xu L, Tao Y, Yang C, Chen X, Fang F, Wu Y, Ding X, Zhao H, Li M, Qian G, Xu Y, Ren J, Du W, Wang J, Lu J, Hu S, Pan J. Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22. PMID: 29048629; PMCID: PMC5780023.
In vivo protocol: 1. Bradshaw-Pierce EL, Pitts TM, Tan AC, McPhillips K, West M, Gustafson DL, Halsey C, Nguyen L, Lee NV, Kan JL, Murray BW, Eckhardt SG. Tumor P-Glycoprotein Correlates with Efficacy of PF-3758309 in in vitro and in vivo Models of Colorectal Cancer. Front Pharmacol. 2013 Mar 22;4:22. doi: 10.3389/fphar.2013.00022. PMID: 23524533; PMCID: PMC3605511. 2. Wang K, Huynh N, Wang X, Baldwin G, Nikfarjam M, He H. Inhibition of p21 activated kinase enhances tumour immune response and sensitizes pancreatic cancer to gemcitabine. Int J Oncol. 2018 Jan;52(1):261-269. doi: 10.3892/ijo.2017.4193. Epub 2017 Nov 7. PMID: 29115428.

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1: Briz V, Baudry M. Estrogen Regulates Protein Synthesis and Actin Polymerization in Hippocampal Neurons through Different Molecular Mechanisms. Front Endocrinol (Lausanne). 2014 Feb 25;5:22. doi: 10.3389/fendo.2014.00022. eCollection 2014. PubMed PMID: 24611062; PubMed Central PMCID: PMC3933789.

2: Fu X, Feng J, Zeng D, Ding Y, Yu C, Yang B. PAK4 confers cisplatin resistance in gastric cancer cells via PI3K/Akt- and MEK/Erk-dependent pathways. Biosci Rep. 2014 Jan 29. [Epub ahead of print] PubMed PMID: 24471762; PubMed Central PMCID: PMC3941610.

3: Ryu BJ, Lee H, Kim SH, Heo JN, Choi SW, Yeon JT, Lee J, Lee J, Cho JY, Kim SH, Lee SY. PF-3758309, p21-activated kinase 4 inhibitor, suppresses migration and invasion of A549 human lung cancer cells via regulation of CREB, NF-κB, and β-catenin signalings. Mol Cell Biochem. 2014 Apr;389(1-2):69-77. doi: 10.1007/s11010-013-1928-8. Epub 2013 Dec 24. PubMed PMID: 24366569.

4: Gao J, Ha BH, Lou HJ, Morse EM, Zhang R, Calderwood DA, Turk BE, Boggon TJ. Substrate and inhibitor specificity of the type II p21-activated kinase, PAK6. PLoS One. 2013 Oct 28;8(10):e77818. doi: 10.1371/journal.pone.0077818. eCollection 2013. PubMed PMID: 24204982; PubMed Central PMCID: PMC3810134.

5: Itakura A, Aslan JE, Kusanto BT, Phillips KG, Porter JE, Newton PK, Nan X, Insall RH, Chernoff J, McCarty OJ. p21-Activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils. PLoS One. 2013 Sep 3;8(9):e73063. doi: 10.1371/journal.pone.0073063. eCollection 2013. PubMed PMID: 24019894; PubMed Central PMCID: PMC3760889.

6: Arias-Romero LE, Villamar-Cruz O, Huang M, Hoeflich KP, Chernoff J. Pak1 kinase links ErbB2 to β-catenin in transformation of breast epithelial cells. Cancer Res. 2013 Jun 15;73(12):3671-82. doi: 10.1158/0008-5472.CAN-12-4453. Epub 2013 Apr 10. PubMed PMID: 23576562; PubMed Central PMCID: PMC3687032.

7: Pitts TM, Kulikowski GN, Tan AC, Murray BW, Arcaroli JJ, Tentler JJ, Spreafico A, Selby HM, Kachaeva MI, McPhillips KL, Britt BC, Bradshaw-Pierce EL, Messersmith WA, Varella-Garcia M, Eckhardt SG. Association of the epithelial-to-mesenchymal transition phenotype with responsiveness to the p21-activated kinase inhibitor, PF-3758309, in colon cancer models. Front Pharmacol. 2013 Mar 28;4:35. doi: 10.3389/fphar.2013.00035. eCollection 2013. PubMed PMID: 23543898; PubMed Central PMCID: PMC3610060.

8: Ong CC, Jubb AM, Jakubiak D, Zhou W, Rudolph J, Haverty PM, Kowanetz M, Yan Y, Tremayne J, Lisle R, Harris AL, Friedman LS, Belvin M, Middleton MR, Blackwood EM, Koeppen H, Hoeflich KP. P21-activated kinase 1 (PAK1) as a therapeutic target in BRAF wild-type melanoma. J Natl Cancer Inst. 2013 May 1;105(9):606-7. doi: 10.1093/jnci/djt054. Epub 2013 Mar 27. PubMed PMID: 23535073.

9: Bradshaw-Pierce EL, Pitts TM, Tan AC, McPhillips K, West M, Gustafson DL, Halsey C, Nguyen L, Lee NV, Kan JL, Murray BW, Eckhardt SG. Tumor P-Glycoprotein Correlates with Efficacy of PF-3758309 in in vitro and in vivo Models of Colorectal Cancer. Front Pharmacol. 2013 Mar 22;4:22. doi: 10.3389/fphar.2013.00022. eCollection 2013. PubMed PMID: 23524533; PubMed Central PMCID: PMC3605511.

10: Chow HY, Jubb AM, Koch JN, Jaffer ZM, Stepanova D, Campbell DA, Duron SG, O'Farrell M, Cai KQ, Klein-Szanto AJ, Gutkind JS, Hoeflich KP, Chernoff J. p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model. Cancer Res. 2012 Nov 15;72(22):5966-75. doi: 10.1158/0008-5472.CAN-12-2246. Epub 2012 Sep 14. PubMed PMID: 22983922; PubMed Central PMCID: PMC3500416.

11: Maruta H. Effective neurofibromatosis therapeutics blocking the oncogenic kinase PAK1. Drug Discov Ther. 2011 Dec;5(6):266-78. PubMed PMID: 22466437.

12: Zhao ZS, Manser E. Do PAKs make good drug targets? F1000 Biol Rep. 2010 Sep 23;2:70. doi: 10.3410/B2-70. PubMed PMID: 21173843; PubMed Central PMCID: PMC2989626.

13: Murray BW, Guo C, Piraino J, Westwick JK, Zhang C, Lamerdin J, Dagostino E, Knighton D, Loi CM, Zager M, Kraynov E, Popoff I, Christensen JG, Martinez R, Kephart SE, Marakovits J, Karlicek S, Bergqvist S, Smeal T. Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9446-51. doi: 10.1073/pnas.0911863107. Epub 2010 May 3. PubMed PMID: 20439741; PubMed Central PMCID: PMC2889050.



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