A pan PKD inhibitor
IC50: A potent protein kinase D (PKD) antagonist with the IC50 of 1, 2.5 and 2 nM for PKD1, PKD2, PKD3 respectively.
CRT 0066101 is a specific inhibitor of all PKD isoforms. Increasingly studies reveals that PKD family members play an important role in regulating several cellular processes and activities, including chromatin organization, Golgi function, gene expression, cell survival, adhesion, motility, differentiation, DNA synthesis and proliferation. By suppressing PKD, CRT 0066101 is supposed to ameliorate symptoms of pancreatic cancer. [1]
In vitro: 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. [1]
In vivo: 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. [1]
Clinical trial: So far, no clinical trial has been conducted.
Reference:
[1]Harikumar KB, Kunnumakkara1 AB, Ochi N, Tong Z, Deorukhkar A, Sung B, Kelland L, Jamieson S, Sutherland R, Raynham T, Charles M, Bagherzadeh A, Foxton C, Boakes A, Farooq M, Maru D, Diagaradjane P, Matsuo Y, Smith J, Gelovani J, Krishnan S, Aggarwal BB, Rozengurt E, Ireson CR, and Guha S.? A novel small-molecule inhibitor of protein kinase d blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther. 2010 May. 9(5): 113646.
Animal experiment: | Mice: Nineteen days after implantation of Panc-1 cells, tumor areas are, on average 0.3 cm2 and are randomized into the following groups (n=8 mice per group): (a) vehicle (control) 5% dextrose administered by oral gavage once daily and (b) 80 mg/kg CRT0066101 dissolved in 5% dextrose administered by oral gavage once daily. Tumors are measured in 2 dimensions every 2 to 3 days by calipers and area is calculated by multiplying length by width. Therapy is given until tumors reached their designated size limits (1.44 cm2) or until day 24 in CRT0066101 treated group. Final tumor areas are compared among groups using a Student's t test and Fisher’s exact test with p<0.05[1]. |
参考文献: [1]. Harikumar KB, et al. A novel small-molecule inhibitor of protein kinase D blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther. 2010 May;9(5):1136-46. | |
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