CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy.
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.
Bao
Rudi
R
Curis, Inc, Cambridge, Massachusetts 02138, USA. rbao@curis.com
Lai
Cheng-Jung
CJ
Qu
Hui
H
Wang
Dagong
D
Yin
Ling
L
Zifcak
Brian
B
Atoyan
Ruzanna
R
Wang
Jing
J
Samson
Maria
M
Forrester
Jeffrey
J
DellaRocca
Steven
S
Xu
Guang-Xin
GX
Tao
Xu
X
Zhai
Hai-Xiao
HX
Cai
Xiong
X
Qian
Changgeng
C
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
D000970:Antineoplastic Agents; D052117:Benzodioxoles; C543177:CUDC 305; D018841:HSP90 Heat-Shock Proteins; D007093:Imidazoles