From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors.

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Zhu J, Huang JW, Tseng PH, Yang YT, Fowble J, Shiau CW, Shaw YJ, Kulp SK, Chen CS

From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors.

Cancer Res. 2004 Jun 15;64(12):4309-18. doi: 10.1158/0008-5472.CAN-03-4063.

PubMed ID

15205346 [ View in PubMed

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Abstract

The blockade of Akt activation through the inhibition of 3-phosphoinositide-dependent kinase-1 (PDK-1) represents a major signaling mechanism whereby celecoxib mediates apoptosis. Celecoxib, however, is a weak PDK-1 inhibitor (IC(50), 48 microM), requiring at least 30 microM to exhibit discernable effects on the growth of tumor cells in vitro. Here, we report the structure-based optimization of celecoxib to develop PDK-1 inhibitors with greater potency in enzyme inhibition and growth inhibition. Kinetics of PDK-1 inhibition by celecoxib with respect to ATP suggest that celecoxib derivatives inhibit PDK-1 by competing with ATP for binding, a mechanism reminiscent to that of many kinase inhibitors. Structure-activity analysis together with molecular modeling was used to generate compounds that were tested for their potency in inhibiting PDK-1 kinase activity and in inducing apoptosis in PC-3 prostate cancer cells. Docking of potent compounds into the ATP-binding site of PDK-1 was performed for lead optimization, leading to two compounds, OSU-03012 and OSU-03013, with IC(50) values in PDK-1 inhibition and apoptosis induction in the low microM range. Exposure of PC-3 cells to these agents led to Akt dephosphorylation and inhibition of p70 S6 kinase activity. Moreover, overexpression of constitutively active forms of PDK-1 and Akt partially protected OSU-03012-induced apoptosis. Screening in a panel of 60 cell lines and more extensive testing in PC-3 cells indicated that the mean concentration for total growth inhibition was approximately 3 microM for both agents. Considering the conserved role of PDK-1/Akt signaling in promoting tumorigenesis, these celecoxib analogs are of translational relevance for cancer prevention and therapy.

DrugBank Data that Cites this Article

Drugs

Celecoxib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Celecoxib	3-phosphoinositide-dependent protein kinase 1	Protein	Humans	Unknown	Inhibitor	Details