Heat shock protein 70 inhibitors. 2. 2,5′-thiodipyrimidines, 5-(phenylthio)pyrimidines, 2-(pyridin-3-ylthio)pyrimidines, and 3-(phenylthio)pyridines as reversible binders to an allosteric site on heat shock protein 70 Journal Article

   

Authors:	Taldone, T.; Kang, Y.; Patel, H. J.; Patel, M. R.; Patel, P. D.; Rodina, A.; Patel, Y.; Gozman, A.; Maharaj, R.; Clement, C. C.; Lu, A.; Young, J. C.; Chiosis, G.
Article Title:	Heat shock protein 70 inhibitors. 2. 2,5′-thiodipyrimidines, 5-(phenylthio)pyrimidines, 2-(pyridin-3-ylthio)pyrimidines, and 3-(phenylthio)pyridines as reversible binders to an allosteric site on heat shock protein 70
Abstract:	The discovery and development of heat shock protein 70 (Hsp70) inhibitors is currently a hot topic in cancer. In the preceding paper in this issue (10.1021/jm401551n), we have described structure-activity relationship studies in the first Hsp70 inhibitor class rationally designed to bind to a novel allosteric pocket located in the N-terminal domain of the protein. These ligands contained an acrylamide to take advantage of an active cysteine embedded in the allosteric pocket and acted as covalent protein modifiers upon binding. Here, we perform chemical modifications around the irreversible inhibitor scaffold to demonstrate that covalent modification is not a requirement for activity within this class of compounds. The study identifies derivative 27c, which mimics the biological effects of the irreversible inhibitors at comparable concentrations. Collectively, the back-to-back manuscripts describe the first pharmacophores that favorably and selectively interact with a never explored pocket in Hsp70 and provide a novel blueprint for a cancer-oriented development of Hsp70-directed ligands. © 2014 American Chemical Society.
Keywords:	controlled study; unclassified drug; human cell; complex formation; cancer cell; binding site; heat shock protein 70; pharmacophore; pyrimidine derivative; human; article; 2 (pyridin 3 ylthio)pyrimidine derivative; 2,5' thiodipyrimidine derivative; 3 (phenylthio)pyridine derivative; 5 (phenylthio)pyrimidine derivative
Journal Title:	Journal of Medicinal Chemistry
Volume:	57
Issue:	4
ISSN:	0022-2623
Publisher:	American Chemical Society
Date Published:	2014-02-27
Start Page:	1208
End Page:	1224
Language:	English
DOI:	10.1021/jm401552y
PROVIDER:	scopus
PMCID:	PMC3983364
PUBMED:	24548239
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84896815426&partnerID=40&md5=67c24adf974fc83c2fcffa57308bcb17
Notes:	Cited By (since 1996):1 -- Export Date: 1 May 2014 -- CODEN: JMCMA -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/50226