Heat shock protein 70 inhibitors. 1. 2,5′-thiodipyrimidine and 5-(phenylthio)pyrimidine acrylamides as irreversible binders to an allosteric site on heat shock protein 70 Journal Article
| Authors: | Kang, Y.; Taldone, T.; Patel, H. J.; Patel, P. D.; Rodina, A.; Gozman, A.; Maharaj, R.; Clement, C. C.; Patel, M. R.; Brodsky, J. L.; Young, J. C.; Chiosis, G. |
| Article Title: | Heat shock protein 70 inhibitors. 1. 2,5′-thiodipyrimidine and 5-(phenylthio)pyrimidine acrylamides as irreversible binders to an allosteric site on heat shock protein 70 |
| Abstract: | Heat shock protein 70 (Hsp70) is an important emerging cancer target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure-activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5′-thiodipyrimidine and 5-(phenylthio)pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives 17a and 20a, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics. © 2014 American Chemical Society. |
| Keywords: | unclassified drug; human cell; apoptosis; cancer cell culture; structure activity relation; cancer inhibition; amino terminal sequence; binding site; heat shock protein 70; drug protein binding; human; article; 2,5' thiodipyrimidine acrylamide derivative; 5 (phenylthio)pyrimidine acrylamide derivative; acrylamide derivative; antineoplastic alkaloid |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 57 |
| Issue: | 4 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2014-02-18 |
| Start Page: | 1188 |
| End Page: | 1207 |
| Language: | English |
| DOI: | 10.1021/jm401551n |
| PROVIDER: | scopus |
| PMCID: | PMC3983365 |
| PUBMED: | 24548207 |
| DOI/URL: | |
| Notes: | Cited By (since 1996):1 -- Export Date: 1 May 2014 -- CODEN: JMCMA -- Source: Scopus |
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