Potent triazolothione inhibitor of heat-shock protein-90.
Heat-shock protein-90 is an attractive target for anticancer drugs, as heat-shock protein-90 blockers such as the ansamycin 17-(allylamino)-17-demethoxygeldanamycin greatly reduce the expression of many signaling molecules that are disregulated in cancer cells and are key drivers of tumor growth and metastasis. While 17-(allylamino)-17-demethoxygeldanamycin has shown promise in clinical trials, this compound class has significant template-related drawbacks. In this paper, we describe a new, potent non-ansamycin small-molecule inhibitor of heat-shock protein-90, BX-2819, containing resorcinol and triazolothione rings. Structural studies demonstrate binding of BX-2819 to the ADP/ATP-binding pocket of heat-shock protein-90. The compound blocked expression of heat-shock protein-90 client proteins in cancer cell lines and inhibited cell growth with a potency similar to 17-(allylamino)-17-demethoxygeldanamycin. In a panel of four cancer cell lines, BX-2819 blocked growth with an average IC(50) value of 32 nM (range of 7-72 nM). Efficacy studies demonstrated that treatment with BX-2819 significantly inhibited the growth of NCI-N87 and HT-29 tumors in nude mice, consistent with pharmacodynamic studies showing inhibition of heat-shock protein-90 client protein expression in tumors for greater than 16 h after dosing. These data support further studies to assess the potential of BX-2819 and related analogs for the treatment of cancer.
Feldman
Richard I
RI
Bayer Healthcare, 2600 Hilltop Drive, Richmond, CA 94804, USA. rick.feldman@bayer.com
Mintzer
Bob
B
Zhu
Daguang
D
Wu
James M
JM
Biroc
Sandra L
SL
Yuan
Shendong
S
Emayan
Kumar
K
Chang
Zheng
Z
Chen
Deborah
D
Arnaiz
Damian O
DO
Bryant
Judi
J
Ge
Xue Snow
XS
Whitlow
Marc
M
Adler
Marc
M
Polokoff
Mark A
MA
Li
Wei-Wei
WW
Ferrer
Mike
M
Sato
Takashi
T
Gu
Jian-Ming
JM
Shen
Jun
J
Tseng
Jih-Lie
JL
Dinter
Harald
H
Buckman
Brad
B
D000818:Animals; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C543002:BX-2819; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D014230:Triazoles; C112765:tanespimycin