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 of Medicinal Chemistry

Volumn 57, Issue 4, 2014, Pages 1208-1224

  Taldone, Tony ^a   Kang, Yanlong ^a,c   Patel, Hardik J ^a   Patel, Maulik R ^a   Patel, Pallav D ^a   Rodina, Anna ^a   Patel, Yogita ^b   Gozman, Alexander ^a,d   Maharaj, Ronnie ^a   Clement, Cristina C ^a,e   Lu, Alvin ^a   Young, Jason C ^b   Chiosis, Gabriela ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b MCGILL UNIVERSITY   (Canada)

^c BioZone Pharmaceuticals Inc   (United States)

^d ALBANY MEDICAL CENTER   (United States)

^e ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (PYRIDIN 3 YLTHIO)PYRIMIDINE DERIVATIVE; 2,5' THIODIPYRIMIDINE DERIVATIVE; 3 (PHENYLTHIO)PYRIDINE DERIVATIVE; 5 (PHENYLTHIO)PYRIMIDINE DERIVATIVE; HEAT SHOCK PROTEIN 70; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BINDING SITE; CANCER CELL; COMPLEX FORMATION; CONTROLLED STUDY; HUMAN; HUMAN CELL; PHARMACOPHORE;

ALLOSTERIC SITE; HSP70 HEAT-SHOCK PROTEINS; LIGANDS; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84896815426     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401552y     Document Type: Article

References (37)

1. Mayer, M. P.; Bukau, B. Hsp70 chaperones: cellular functions and molecular mechanism Cell. Mol. Life Sci. 2005, 62, 670-684
2. Bukau, B.; Weissman, J.; Horwich, A. Molecular chaperones and protein quality control Cell 2006, 125, 443-451
3. Powers, M. V.; Jones, K.; Barillari, C.; Westwood, I.; van Montfort, R. L.; Workman, P. Targeting HSP70: the second potentially druggable heat shock protein and molecular chaperone? Cell Cycle 2010, 9, 1542-1550
4. Rerole, A.-L.; Jego, G.; Garrido, C. Hsp70: anti-apoptotic and tumorigenic protein Methods Mol. Biol. 2011, 787, 205-229
5. Brodsky, J. F.; Chiosis, G. Hsp70 molecular chaperones: emerging roles in human disease and identification of small molecule modulators Curr. Top. Med. Chem. 2006, 6, 1215-1225
6. Pratt, W. B.; Toft, D. O. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery Exp. Biol. Med. (Maywood, NJ, U. S.) 2003, 228, 111-133
7. Wegele, H.; Müller, L.; Buchner, J. Hsp70 and Hsp90-a relay team for protein folding Rev. Physiol. Biochem. Pharmacol. 2004, 151, 1-44
8. Taipale, M.; Jarosz, D. F.; Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights Nat. Rev. Mol. Cell Biol. 2010, 11, 515-528
9. Trepel, J.; Mollapour, M.; Giaccone, G.; Neckers, L. Targeting the dynamic HSP90 complex in cancer Nat. Rev. Cancer 2010, 10, 537-549
10. Garrido, C.; Brunet, M.; Didelot, C.; Zermati, Y.; Schmitt, E.; Kroemer, G. Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties Cell Cycle 2006, 5, 2592-2601
11. Powers, M. V.; Clarke, P. A.; Workman, P. Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis Cancer Cell 2008, 14, 250-262
12. Patury, S.; Miyata, Y.; Gestwicki, J. E. Pharmacological targeting of the Hsp70 chaperone Curr. Top. Med. Chem. 2009, 9, 1337-1351
13. Evans, C. G.; Chang, L.; Gestwicki, J. E. Heat shock protein 70 (hsp70) as an emerging drug target J. Med. Chem. 2010, 53, 4585-4602
14. 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. 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. J. Med. Chem. 2014, DOI: 10.1021/jm401551n.
15. Rodina, A.; Patel, P. D.; Kang, Y.; Patel, Y.; Baaklini, I.; Wong, M. J. H.; Taldone, T.; Yan, P.; Yang, C.; Maharaj, R.; Gozman, A.; Patel, M. R.; Patel, H. J.; Chirico, W.; Erdjument-Bromage, H.; Talele, T. T.; Young, J. C.; Chiosis, G. Identification of an allosteric pocket on human Hsp70 reveals a mode of inhibition of this therapeutically important protein Chem. Biol. 2013, 20, 1469-1480
16. Zou, J.; Guo, Y.; Guettouche, T.; Smith, D. F.; Voellmy, R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1 Cell 1998, 94, 471-480
17. Barf, T.; Kaptein, A. Irreversible protein kinase inhibitors: balancing the benefits and risks J. Med. Chem. 2012, 55, 6243-6262
18. Singh, J.; Petter, R. C.; Baillie, T. A.; Whitty, A. The resurgence of covalent drugs Nat. Rev. Drug Discovery 2011, 10, 307-317
19. Ma, J. C.; Dougherty, D. A. The cation-π interaction Chem. Rev. 1997, 97, 1303-1324
20. Gallivan, J. P.; Dougherty, D. A. Cation-π interactions in structural biology Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 9459-9464
21. Crowley, P. B.; Golovin, A. Cation-π interactions in protein-protein interfaces Proteins 2005, 59, 231-239
22. Meyer, E. A.; Castellano, R. K.; Diederich, F. Interactions with aromatic rings in chemical and biological recognition Angew. Chem., Int. Ed. 2003, 42, 1210-1250
23. Salonen, L. M.; Ellermann, M.; Diederich, F. Aromatic rings in chemical and biological recognition: energetics and structures Angew. Chem., Int. Ed. 2011, 50, 4808-4842
24. Sörme, P.; Arnoux, P.; Kahl-Knutsson, B.; Leffler, H.; Rini, J. M.; Nilsson, U. J. Structural and thermodynamic studies on cation-π interactions in lectin-ligand complexes: high-affinity galectin-3 inhibitors through fine-tuning of an arginine-arene interaction J. Am. Chem. Soc. 2005, 127, 1737-1743
25. Mecozzi, S.; West, J. A. P.; Dougherty, D. A. Cation-π interactions in aromatics of biological and medicinal interest: electrostatic potential surfaces as a useful qualitative guide Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 10566-10571
26. Morgan, R. S.; Tatsch, C. E.; Gushard, R. H.; McAdon, J.; Warme, P. K. Chains of alternating sulfur and pi-bonded atoms in eight small proteins Int. J. Pept. Protein Res. 1978, 11, 209-217
27. Furet, P.; Bold, G.; Meyer, T.; Roesel, J.; Guagnano, V. Aromatic interactions with phenylalanine 691 and cysteine 828: a concept for FMS-like tyrosine kinase-3 inhibition. application to the discovery of a new class of potential antileukemia agents J. Med. Chem. 2006, 49, 4451-4454
28. Tsou, H. R.; Mamuya, N.; Johnson, B. D.; Reich, M. F.; Gruber, B. C.; Ye, F.; Nilakantan, R.; Shen, R.; Discafani, C.; DeBlanc, R.; Davis, R.; Koehn, F. E.; Greenberger, L. M.; Wang, Y. F.; Wissner, A. 6-Substituted-4-(3- bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity J. Med. Chem. 2001, 44, 2719-2734
29. Wissner, A.; Overbeek, E.; Reich, M. F.; Floyd, M. B.; Johnson, B. D.; Mamuya, N.; Rosfjord, E. C.; Discafani, C.; Davis, R.; Shi, X.; Rabindran, S. K.; Gruber, B. C.; Ye, F.; Hallett, W. A.; Nilakantan, R.; Shen, R.; Wang, Y. F.; Greenberger, L. M.; Tsou, H. R. Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2) J. Med. Chem. 2003, 46, 49-63
30. Tsou, H. R.; Overbeek-Klumpers, E. G.; Hallett, W. A.; Reich, M. F.; Floyd, M. B.; Johnson, B. D.; Michalak, R. S.; Nilakantan, R.; Discafani, C.; Golas, J.; Rabindran, S. K.; Shen, R.; Shi, X.; Wang, Y. F.; Upeslacis, J.; Wissner, A. Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3- carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity J. Med. Chem. 2005, 48, 1107-1131
31. Carmi, C.; Galvani, E.; Vacondio, F.; Rivara, S.; Lodola, A.; Russo, S.; Aiello, S.; Bordi, F.; Costantino, G.; Cavazzoni, A.; Alfieri, R. R.; Ardizzoni, A.; Petronini, P. G.; Mor, M. Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides J. Med. Chem. 2012, 55, 2251-2264
32. Young, J. C.; Agashe, V. R.; Siegers, K.; Hartl, F. U. Pathways of chaperone-mediated protein folding in the cytosol Nat. Rev. Mol. Cell Biol. 2004, 5, 781-791
33. Bhangoo, M. K.; Tzankov, S.; Fan, A. C.; Dejgaard, K.; Thomas, D. Y.; Young, J. C. Multiple 40-kDa heat shock protein chaperones function in Tom70-dependent mitochondrial import Mol. Biol. Cell 2007, 18, 3414-3428
34. Tzankov, S.; Wong, M. J. H.; Shi, K.; Nassif, C.; Young, J. C. Functional divergence between co-chaperones of Hsc70 J. Biol. Chem. 2008, 283, 27100-27109
35. Baaklini, I.; Wong, M. J.; Hantouche, C.; Patel, Y.; Shrier, A.; Young, J. C. The DNAJA2 substrate release mechanism is essential for chaperone-mediated folding J. Biol. Chem. 2012, 287, 41939-41954
36. Du, Y.; Moulick, K.; Rodina, A.; Aguirre, J.; Felts, S.; Dingledine, R.; Fu, H.; Chiosis, G. High-throughput screening fluorescence polarization assay for tumor-specific Hsp90 J. Biomol. Screening 2007, 12, 915-924
37. Rodina, A.; Vilenchik, M.; Moulick, K.; Aguirre, J.; Kim, J.; Chiang, A.; Litz, J.; Clement, C. C.; Kang, Y.; She, Y.; Wu, N.; Felts, S.; Wipf, P.; Massague, J.; Jiang, X.; Brodsky, J. L.; Krystal, G. W.; Chiosis, G. Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer Nat. Chem. Biol. 2007, 3, 498-507