Celebrex was reported to induce apoptosis in the prostate cancer cell line PC-3 at 50µM. Early research from our laboratory demonstrated that this apoptotic inducing effect was independent of its COX-2 inhibitory activity. Further investigation showed that PDK-1 was a major protein targeted by celebrex in PC-3 cells to induce apoptosis. However, celebrex was very weak in inhibiting PDK-1 with IC50 of 48µM. To improve its potency, two series of analogs were designed and synthesized. In the first series of 24 compounds, the 5-position methylphenyl moiety of celebrex was replaced by various aromatic ring systems to explore the optimal hydrophobic group. OSU02067 (IC50=9µM) with phenanthrene at the 5-position was the best inhibitor among this series and was selected as the lead compound for further modification. Enzyme kinetics study of PDK-1 inhibition by celebrex indicated that it competed with ATP for binding. Docking of OSU02067 into the ATP binding domain of PDK-1 showed that the sulfonamide moiety hydrogen bonded to hinge region residue Ala162. Considering the importance of H-bonding, the sulfonamide moiety was substituted with various heteroatom-rich functional groups in the 2nd series of 12 compounds. OSU03012 and OSU03013 stood out as the most potent analogs with IC50s of 5µM and 2µM, respectively. Such improvement was partly attributed to an additional H-bond formed with hinge region residue Ser160. Exposure of PC-3 cells to these two agents (5µM or higher) led to significant decreases in Akt and p70s6k kinase activity (both are downstream substrates of PDK-1) and an increase in apoptosis evidenced by nucleosome formation and PARP cleavage. As OSU03012 was tolerated well by nude mice at a dose of 200mg/kg, it was chosen to be studied in many different cancers, including leukemia, breast, lung, thyroid, ovarian and bladder cancers. Preclinical studies are underway. Future structure modification of OSU03012 is necessary to further improve the binding affinity for PDK-1.