2. Academic Validation
  3. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1

Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1

  • J Biol Chem. 2005 May 20;280(20):19867-74. doi: 10.1074/jbc.M501367200.
Richard I Feldman 1,  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,  Marc Adler,  Silke Finster,  Zheng Chang,  Damian O Arnaiz
Affiliations

Affiliation

  • 1 Departments of Cancer Research, Berlex Biosciences, Richmond, California 94804, USA. rick_feldman@berlex.com
PMID: 15772071 DOI: 10.1074/jbc.M501367200
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.

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