Structural Optimization of Celecoxib for Chemoprevention

Cellsignals, Inc., Columbus OH

Investigators

Abstract

DESCRIPTION (provided by applicant): This project is aimed at developing a novel class of molecularly targeted agents for cancer prevention. The lead compound OSU-02067 was developed in our laboratory by using celecoxib as a molecular starting point via computer modeling-based structural analysis. Previously, we demonstrated that the ability of celecoxib to arrest cell cycle, activate apoptosis, and inhibit angiogenesis is independent of cyclooxygenase-2 (COX-2) inhibition, and is primarily attributable to the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling. The biological importance of the PDK-1/Akt signaling pathway in carcinogenesis provides a molecular rationale to justify its inhibition as a viable strategy to chemoprevention. Consequently, we have synthesized over one hundred celecoxib derivatives for testing PDK-1 inhibitory activity and apoptosisinducing activity in PC-3 human androgen-independent prostate cancer cells. In vitro and in vivo testing of a panel of lead compounds led to the selection of a structurally optimized agent OSU-02067. OSU-02067 inhibits the proliferation of PC-3 prostate cancer cells as low as 0.5 microM (vis-a-vis 30 microM for celecoxib), and is effective in inhibiting the growth of PC-3 xenograft in nude mice. More noteworthy is that it could be orally dosed to provide serum concentrations exceeding 20 microM without demonstrable toxicity, compatible with chronic use for chemoprevention. Thus, this proposal consists of two pecific aims. Aim 1 is to use OSU-02067 as a lead to continue the development of the 3rd-generation celecoxib derivatives with enhanced activity in inhibiting PDK-1/Akt signaling. Based on our working model, we will focus on enhancing the electronegative potential surrounding the heterocyclic system to augment its interactions with the enzyme pocket. Our goal is to lower the IC50 for inhibiting PDK-1/Akt signaling to the sub-microM level. Aim 2 is to assess the in vitro antitumor effect of OSU-02067 and selected 3rd-generation analogues in different cancer cell lines. Akt kinase activities and various biomarkers pertinent to cell cycle arrest and apoptosis will be examined to understand the underlying mechanism. These findings will serve as the basis for submission of a Phase II grant proposal in support of our long-term goal to develop a novel class of agents that target PDK-1/Akt signaling for cancer prevention.