CRT0066101 dihydrochloride是一种选择性PKD有效抑制剂，对PKD1、2和3的IC50值分别为1、2.5和2 nM。

CRT0066101 dihydrochloride is an effective and selective PKD inhibitor (IC50s: 1, 2.5 and 2 nM for PKD1, 2, and 3).

CRT0066101 specifically blocks PKD1/2 activity and does not suppress PKCα/PKCβ/PKCε activity in multiple cancer cell types including A549 and MiaPaCa-2. CRT0066101 significantly inhibits Panc-1 cell proliferation (IC50: 1 μM). Treatment with CRT0066101 results in a 6-10 fold induction of apoptosis in Panc-1 cells. CRT0066101 significantly reduces cell proliferation of Panc-1, Colo357, MiaPaCa-2, and AsPC-1 cells but has a modest effect in Capan-2 cells. CRT0066101 (5 μM) blocks both the basal and NT-induced pS916-PKD1/2 (activated PKD1/2) in Panc-1 and Panc-28 cells. CRT0066101 reduces PKD-dependent NF-κB activation and NF-κB-dependent gene expressions in Panc-1.

Optimal therapeutic concentrations (8 μM) of CRT0066101 are detectable 6 h after oral administration of this drug. CRT0066101 given orally (80 mg/kg/day) for 28 days significantly abrogates PaCa growth in Panc-1 subcutaneous xenograft model. Activated PKD1/2 expression in the treated tumor-explants is significantly inhibited with peak tumor concentration (12 μM) of CRT0066101 achieved within 2 h after oral administration. Further, CRT0066101 given orally (80 mg/kg/day) for 21 days in Panc-1 orthotopic model potently blocks tumor growth in vivo. CRT0066101 significantly reduces Ki-67+ proliferation index, increases TUNEL+ apoptotic cells, and abrogates expression of NF-κB-dependent proteins including cyclin D1, survivin, and cIAP-1.

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 the 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.

1883545-60-5

C18H24Cl2N6O

411.33

CRT0066101二盐酸盐

DMSO:23 mg/mL (55.92 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years