title: Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1.
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.
authors.affiliation: Departments of Cancer Research, Berlex Biosciences, Richmond, California 94804, USA. rick_feldman@berlex.com
authors.forename: Richard I
authors.initials: RI
authors.lastname: Feldman
authors.forename: James M
authors.initials: JM
authors.lastname: Wu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Polokoff
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Kochanny
authors.forename: Harald
authors.initials: H
authors.lastname: Dinter
authors.forename: Daguang
authors.initials: D
authors.lastname: Zhu
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Biroc
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.forename: Judi
authors.initials: J
authors.lastname: Bryant
authors.forename: Shendong
authors.initials: S
authors.lastname: Yuan
authors.forename: Brad O
authors.initials: BO
authors.lastname: Buckman
authors.forename: Dao
authors.initials: D
authors.lastname: Lentz
authors.forename: Mike
authors.initials: M
authors.lastname: Ferrer
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Silke
authors.initials: S
authors.lastname: Finster
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chang
authors.forename: Damian O
authors.initials: DO
authors.lastname: Arnaiz
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005260:Female; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494918:AKT1 protein, human; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt