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Protein Kinase D inhibitor CRT0066101 Small Molecule (Tool Compound)

Invented by Dr Mark Charles at Cancer Research Technology

Info

Catalogue Number 151831
Antigen/Gene or Protein Targets Protein Kinase D (PKD)
Type Inhibitor
Relevance The Protein Kinase D inhibitor CRT0066101 is a potent antitumoral agent in vitro and in vivo. Protein kinase D (PKD) is an evolutionarily conserved protein kinase family with structural, enzymological, and regulatory properties different from the PKC family members. Signaling through PKD is induced by a remarkable number of stimuli, including G-protein-coupled receptor agonists and polypeptide growth factors. PKD1, the most studied member of the family, is increasingly implicated in the regulation of a complex array of fundamental biological processes, including signal transduction, cell proliferation and differentiation, membrane trafficking, secretion, immune regulation, cardiac hypertrophy and contraction, angiogenesis, and cancer. PKD mediates such a diverse array of normal and abnormal biological functions via dynamic changes in its spatial and temporal localization, combined with its distinct substrate specificity. Studies on PKD thus far indicate a striking diversity of both its signal generation and distribution and its potential for complex regulatory interactions with multiple downstream pathways, often regulating the subcellular localization of its targets.
On Target IC50 IC50 1, 2 and 2.5 nM for PKD1, PKD3 and PKD2 respectively
Selectivity Selectivity for PKD against a panel of >90 protein kinases, including PKCα, MEK, ERK, c-Raf and c-Src.
Molecular Formula C18H23CIN6
lUPAC 2-[4-((R)-2-Amino-butylamino)-pyrimidin-2-yl]-4-(1-methyl-1Hpyrazol-4-yl)-phenol; hydrochloride
Molecular Weight (g/mol) 374.86776
In vivo applications In Panc-1 subcutaneous xenograft model, orally administration of CRT0066101 at the dosage of 80 mg/kg/d for 24 days significantly suppressed pancreatic cancer growth. Moreover, when CRT0066101 reached its peak concentration (12 μmol/L) in tumor model, the expression of activated PKD1/2 in the treated tumor explants was substantially decreased. It was concluded that CRT0066101 given orally at 80 mg/kg/d for 21 days in Panc-1 orthotropic model suppressed tumor growth potently in vivo.
Clinical trial: So far, no clinical trial has been conducted.
In vitro applications In Panc-1 cell line based assays, CRT0066101 was reported to reduce bromodeoxyuridine incorporation; increase cell apoptosis; suppress neurotensin-induced PKD1/2 activation; block neurotensin-induced Hsp27 phosphorylation; interrupt PKD1-mediated NF-κB activation as well as down-regulate expression of NF-κB-dependent proliferative and pro-survival proteins.
Research Area Cell Signaling & Signal Transduction
Notes Using Panc-1 as a model system, it has been demonstrated that CRT0066101:

• Reduced bromodeoxyuridine incorporation
• Increased apoptosis
• Blocked neurotensin-induced PKD1/2 activation
• Reduced neurotensin-induced, PKD-mediated Hsp27 phosphorylation
• Attenuated PKD1-mediated NF-κB activation
• Abrogated the expression of NF-κB-dependent proliferative and pro-survival proteins


Molecular Weight:
374.86776 (HCl salt)
338.40712 (free base) g/mol

References: 7 entries

Ryvkin et al. 2015. J Biol Chem. 290(17):11199-208. PMID: 25802335.

Wei et al. 2014. Mol Cancer Ther. 13(5):1130-41. PMID: 24634417.

Bernhart et al. 2013. Exp Cell Res. 319(13):2037-48. PMID: 23562655.

Yang et al. 2013. Proc Natl Acad Sci U S A. 110(6):2312-7. PMID: 23345428.

Yuan et al. 2012. Front Physiol. 3:60. PMID: 22470346.

Ochi et al. 2011. J Cell Physiol. 226(4):1074-81. PMID: 20857418.

Harikumar et al. 2010. Mol Cancer Ther. 9(5):1136-46. PMID: 20442301.


Add a reference

References: 7 entries

Ryvkin et al. 2015. J Biol Chem. 290(17):11199-208. PMID: 25802335.

Wei et al. 2014. Mol Cancer Ther. 13(5):1130-41. PMID: 24634417.

Bernhart et al. 2013. Exp Cell Res. 319(13):2037-48. PMID: 23562655.

Yang et al. 2013. Proc Natl Acad Sci U S A. 110(6):2312-7. PMID: 23345428.

Yuan et al. 2012. Front Physiol. 3:60. PMID: 22470346.

Ochi et al. 2011. J Cell Physiol. 226(4):1074-81. PMID: 20857418.

Harikumar et al. 2010. Mol Cancer Ther. 9(5):1136-46. PMID: 20442301.


Add a reference

References: 7 entries

Ryvkin et al. 2015. J Biol Chem. 290(17):11199-208. PMID: 25802335.

Wei et al. 2014. Mol Cancer Ther. 13(5):1130-41. PMID: 24634417.

Bernhart et al. 2013. Exp Cell Res. 319(13):2037-48. PMID: 23562655.

Yang et al. 2013. Proc Natl Acad Sci U S A. 110(6):2312-7. PMID: 23345428.

Yuan et al. 2012. Front Physiol. 3:60. PMID: 22470346.

Ochi et al. 2011. J Cell Physiol. 226(4):1074-81. PMID: 20857418.

Harikumar et al. 2010. Mol Cancer Ther. 9(5):1136-46. PMID: 20442301.


Add a reference


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