title: Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP.
abstract: We reviewed preclinical data and clinical development of MDM2 (murine double minute 2), ALK (anaplastic lymphoma kinase) and PARP (poly [ADP-ribose] polymerase) inhibitors. MDM2 binds to p53, and promotes degradation of p53 through ubiquitin-proteasome degradation. JNJ-26854165 and RO5045337 are 2 small-molecule inhibitors of MDM2 in clinical development. ALK is a transmembrane protein and a member of the insulin receptor tyrosine kinases. EML4-ALK fusion gene is identified in approximately 3-13% of non-small cell lung cancer (NSCLC). Early-phase clinical studies with Crizotinib, an ALK inhibitor, in NSCLC harboring EML4-ALK have demonstrated promising activity with high response rate and prolonged progression-free survival. PARPs are a family of nuclear enzymes that regulates the repair of DNA single-strand breaks through the base excision repair pathway. Randomized phase II study has shown adding PARP-1 inhibitor BSI-201 to cytotoxic chemotherapy improves clinical outcome in patients with triple-negative breast cancer. Olaparib, another oral small-molecule PARP inhibitor, demonstrated encouraging single-agent activity in patients with advanced breast or ovarian cancer. There are 5 other PARP inhibitors currently under active clinical investigation.
authors.affiliation: Division of Medical Oncology and Hematology, Loma Linda University Medical Center, Loma Linda, CA 92354, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Liao
authors.forename: Chung-Tsen
authors.initials: CT
authors.lastname: Hsueh
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Mirshahidi
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases