7'-substituted benzothiazolothio- and pyridinothiazolothio-purines as potent heat shock protein 90 inhibitors.
We report on the discovery of benzo- and pyridino- thiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a 7'-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity in a Her-2 degradation assay (28-150 nM), good aqueous solubility, and oral bioavailability profiles in mice. In vivo efficacy experiments demonstrate that compounds of this class inhibit tumor growth in an N87 human colon cancer xenograft model via oral administration as shown with compound 37 (8-(7-chlorobenzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-ethyl)-9H- purin-6-ylamine).
Zhang
Lin
L
Department of Medicinal Chemistry, Conforma Therapeutics Corporation, 9393 Towne Centre Drive, Suite 240, San Diego, California 92121, USA. lzhang@conformacorp.com
Fan
Junhua
J
Vu
Khang
K
Hong
Kevin
K
Le Brazidec
Jean-Yves
JY
Shi
Jiandong
J
Biamonte
Marco
M
Busch
David J
DJ
Lough
Rachel E
RE
Grecko
Roy
R
Ran
Yingqing
Y
Sensintaffar
John L
JL
Kamal
Adeela
A
Lundgren
Karen
K
Burrows
Francis J
FJ
Mansfield
Robert
R
Timony
Gregg A
GA
Ulm
Edgar H
EH
Kasibhatla
Srinivas R
SR
Boehm
Marcus F
MF
D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011687:Purines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D018841:HSP90 Heat-Shock Proteins; D011687:Purines; D013438:Sulfhydryl Compounds