title: CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy.
abstract: OBJECTIVE
  We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types.
  
  
  METHODS
  The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models.
  
  
  RESULTS
  CUDC-305 shows high affinity for HSP90alpha/beta (IC(50), approximately 100 nmol/L) and HSP90 complex derived from cancer cells (IC(50), 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC(50), 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross blood-brain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dose-dependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non-small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models.
  
  
  CONCLUSIONS
  CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.
authors.affiliation: Curis, Inc, Cambridge, Massachusetts 02138, USA. rbao@curis.com
authors.forename: Rudi
authors.initials: R
authors.lastname: Bao
authors.forename: Cheng-Jung
authors.initials: CJ
authors.lastname: Lai
authors.forename: Hui
authors.initials: H
authors.lastname: Qu
authors.forename: Dagong
authors.initials: D
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Yin
authors.forename: Brian
authors.initials: B
authors.lastname: Zifcak
authors.forename: Ruzanna
authors.initials: R
authors.lastname: Atoyan
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Maria
authors.initials: M
authors.lastname: Samson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Forrester
authors.forename: Steven
authors.initials: S
authors.lastname: DellaRocca
authors.forename: Guang-Xin
authors.initials: GX
authors.lastname: Xu
authors.forename: Xu
authors.initials: X
authors.lastname: Tao
authors.forename: Hai-Xiao
authors.initials: HX
authors.lastname: Zhai
authors.forename: Xiong
authors.initials: X
authors.lastname: Cai
authors.forename: Changgeng
authors.initials: C
authors.lastname: Qian
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; C543177:CUDC 305; D018841:HSP90 Heat-Shock Proteins; D007093:Imidazoles