N-[3-[[5-Bromo-4-[[2-(1H-imidazol-4-yl)ethyl]amino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide

potent PDK1 inhibitors IC50 = 6 nM

Chemical Formula: C20H23BrN8O

Molecular Weight: 471.4

OTAVAchemicals Catalogue Number: 7070707060

CAS Registry Number: 304896-28-4

Purity: 97% (HPLC)

Ref.: Feldman et al. Novel Small Molecule Inhibitors of 3-Phosphoinositide-dependent Kinase-1. Journal of Biological Chemistry (2005), 280, 19867-19874

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.

DOI: 10.1074/jbc.M501367200