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Novel Small Molecule Inhibitors of 3-phosphoinositide-dependent kinase-1

Novel Small Molecule Inhibitors of 3-phosphoinositide-dependent kinase-1

Richard I Feldman, James M Wu, Mark A Polokoff, Monica J Kochanny, Harald Dinter, Daguang Zhu, Sandra L Biroc, Bruno Alicke, Judi Bryant, Shendong Yuan, Brad O Buckman, Dao Lentz, Mike Ferrer, Marc Whitlow, etc.

J Biol Chem. 2005 May 20;280(20):19867-74.

PMID: 15772071

Abstract:

The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP702674564	BX-912		702674-56-4	Price

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