Tony Taldone, PhD

Senior Research Scientist

Lab Phone

646-888-3180

Email

taldonet@mskcc.org

I am a trained medicinal chemist currently working in the laboratory of Dr. Gabriela Chiosis at Memorial Sloan Kettering Cancer Center as a research faculty. During the past nine years, I have been working to develop novel therapeutics targeting heat shock proteins, such as Hsp90, Hsp70 and Grp94, involved in cell stress and survival which may play a critical role in the development of cancer and potentially other diseases. We take a chemical biology approach to investigate heat shock proteins with the ultimate goal of translating agents into the clinic for the treatment of human diseases. In this regard, my expertise in designing and synthesizing small-molecule inhibitors as well as biological probes for these targets has been critical to the successful outcomes of our research projects. I have an extensive knowledge of chemistry and an understanding of its proper application for establishing structure activity relationships (SAR) as well as a keen understanding of what is required to transform a molecule into a drug. I have also acquired knowledge of cancer biology and a belief that it is the biology which drives the successful development of any drug discovery program. I feel that my qualifications and experience to date put me in a position to uniquely impact the field and to potentially provide cures to cancer.

In an effort to better understand HSP tumor biology with the ultimate purpose of clinical translation of these agents, my research has focused on the design and synthesis of small-molecule inhibitors and chemical tools useful for detailed biological studies. Efforts thus far have resulted in one agent, PU-H71, a potent inhibitor of Hsp90, to enter into clinical trials in patients with advanced solid tumors, lymphoma and myeloproliferative disorders. Additionally, we have developed an assay utilizing a radiolabeled version of the clinical agent referred to as PU-PET, which is intended as a companion diagnostic for Hsp90 inhibition therapy. This agent, 124I-PU-H71, has also entered into clinical trials as a non-invasive means to determine tumor pharmacokinetics and intra-tumoral concentration through PET imaging. PU-PET has the potential to determine those patients which might benefit from Hsp90 inhibitor therapy and therefore offers a powerful tool for successful clinical outcomes.

My direct association with the development of these clinical trials has given me a more profound understanding of the term “bench to bedside”. My research has also contributed towards the discovery and optimization of a Grp94-selective inhibitor and a novel class of small-molecule Hsp70 inhibitors which are currently undergoing evaluation for efficacy in pre-clinical models of cancer. During this period I have also been involved in a multitude of collaborative efforts. I have provided our collaborators with mg to gram amounts of small molecule inhibitors for which I have developed suitable scale-up synthetic methods, formulations for their proper in vivo use and have established conditions for their proper use and storage.

Publications


  1. Lengyel, I.; Cesare, V.; Karram, H.; Taldone, T. About 1-triphenylmethyl-3-tert-butylaziridinone and some of its reactions. J. Heterocyclic Chem. 2001, 38, 997-1002.

  2. Lengyel, I.; Cesare, V.; Taldone, T. About the reaction of 2,3-dibromo-2-methyl-N-(1-adamantyl)-propanamide with sodium tert-butoxide. A competition experiment. Synthetic Commun. 2001, 31, 2499-2506.

  3. Lengyel, I.; Cesare, V.; Taldone, T.; Uliss, D. The synthesis, physical, and spectral properties, and some reactions of a new stable bis-α-lactam (aziridinone) with a terpene skeleton. Synthetic Commun. 2001, 31, 3671-3683.

  4. Lengyel, I.; Cesare, V.; Adam, I.; Taldone, T. About four new trityl-substituted α-lactams. Heterocycles 2002, 57, 73-95.

  5. Lengyel, I.; Cesare, V.; Chen, S.; Taldone, T. About the factors which govern the ring-opening of α-lactams with benzylamine: I. The relative stability of the α-lactam and the substituent on nitrogen. Heterocycles 2002, 57, 677-695.

  6. Cesare, V.; Taldone, T.; Lengyel, I. About the factors which govern the ring-opening of α-lactams with primary amines: II. The relative basicity of the amine. Heterocycles 2002, 57, 1851-1868.

  7. Lengyel, I.; Cesare, V.; Taldone, T. A direct link between the Passerini reaction and α-lactams. Tetrahedron 2004, 60, 1107-1124.

  8. Taldone, T.; Zito, S. W.; Talele, T. T. Inhibition of dipeptidyl peptidase-IV (DPP-IV) by atorvastatin. Bioorg. Med. Chem. Lett. 2008, 18, 479-484.

  9. Lengyel, I.; Taldone, T.; Lyons, T.; Cesare, V. Full characterization and some reactions of 1-(2-adamantyl)-3-(1-adamantyl)aziridin-2-one. J. Heterocyclic Chem. 2008, 45, 803-810.

  10. Shinde, J.; Taldone, T.; Barletta, M.; Kunaparaju, N.; Hu, B.; Kumar, S.; Placido, J.; Zito, S. W. α-Glucosidase inhibitory activity of Syzygium cumini (Linn.) Skeels seed kernel in vitro and in Goto-Kakizaki (GK) rats. Carbohyd. Res. 2008, 343, 1278-1281.

  11. Kang, Y.; Taldone, T.; Clement, C. C.; Fewell, S. W.; Aguirre, J.; Brodsky, J. L.; Chiosis, G. Design of a fluorescence polarization assay platform for the study of human Hsp70. Bioorg. Med. Chem. Lett. 2008, 18, 3749-3751.

  12. Zito, S. W.; Shinde, J.; Chen, I.-C. S.; Taldone, T.; Barletta, M. Oral hypoglycemics: A review of chemicals used to treat type 2 diabetes. Curr. Bioact. Compd. 2008, 4, 68-85.

  13. Taldone, T.; Gozman, A.; Maharaj, R.; Chiosis, G. Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr. Opin. Pharmacol. 2008, 8, 370-374.

  14. Tao, H.; Kang, Y.; Taldone, T.; Chiosis, G. Microwave-assisted one step synthesis of 8-arylmethyl-9H-purin-6-amines. Bioorg. Med. Chem. Lett. 2009, 19, 415-417.

  15. Taldone, T.; Sun, W.; Chiosis, G. Discovery and development of heat shock protein 90 inhibitors. Bioorg. Med. Chem. 2009, 17, 2225-2235.

  16. Caldas-Lopes, E.; Cerchietti, L.; Ahn, J. H.; Clement, C. C.; Robles, A. I.; Rodina, A.; Moulick, K.; Taldone, T.; Gozman, A.; Guo, Y.; Wu, N.; de Stanchina, E.; White, J.; Gross, S. S.; Ma, Y.; Varticovski, L.; Melnick, A.; Chiosis, G. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. P. Natl. Acad. Sci. USA. 2009, 106, 8368-8373.

  17. Taldone, T.; Chiosis, G. Purine-scaffold Hsp90 inhibitors. Curr. Top. Med. Chem. 2009, 9, 1436-1446.

  18. Taldone, T.; Zatorska, D.; Kang, Y.; Chiosis, G. A facile and efficient synthesis of d6-labelled PU-H71, a purine scaffold Hsp90 inhibitor. J. Labelled Compd. Rad. 2010, 53, 47-49.

  19. Holland, J. P.; Caldas-Lopes, E.; Divilov, V.; Longo, V. A.; Taldone, T.; Zatorska, D.; Chiosis, G.; Lewis, J. S. Measuring the pharmacodynamic effects of a novel Hsp90 inhibitor on HER2/neu expression in mice using 89Zr-DFO-trastuzumab. PLoS One, 2010, 5, e8859.

  20. Wrona, I. E.; Gozman, A.; Taldone, T.; Chiosis, G.; Panek, J. S. Synthesis of Reblastatin, Autolytimycin, and Non-Benzoquinone Analogues: Potent Inhibitors of Heat Shock Protein 90 (Hsp90). J. Org. Chem. 2010, 75, 2820-2835.

  21. Taldone, T.; Gillan, V.; Sun, W.; Rodina, A.; Patel, P.; Maitland, K.; O’Neill, K.; Chiosis, G.; Devaney, E. Assay Strategies for the Discovery and Validation of Therapeutics Targeting Brugia pahangi Hsp90. PLoS Neglect. Trop. D. 2010, 4, e714.

  22. Luo, W.; Sun, W.; Taldone, T.; Rodina, A.; Chiosis, G. Heat shock protein 90 in neurodegenerative diseases. Mol. Neurodegener. 2010, 5, 24.

  23. Marubayashi, S.; Koppikar, P.; Taldone, T.; Abdel-Wahab, O.; West, N.; Bhagwat, N.; Caldas-Lopes, E.; Ross, K. N.; Gönen, M.; Gozman, A.; Ahn, J. H.; Rodina, A.; Ouerfelli, O.; Yang, G.; Hedvat, C.; Bradner, J. E.; Chiosis, G.; Levine, R. L. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J. Clin. Invest. 2010, 120, 3578–3593.

  24. Taldone, T.; Zatorska, D.; Patel, P. D.; Zong, H.; Rodina, A.; Ahn, J. H.; Moulick, K.; Guzman, M. L.; Chiosis, G. Design, synthesis, and evaluation of small molecule Hsp90 probes. Bioorg. Med. Chem. 2011, 19, 2603–2614.

  25. Patel, H. J.; Modi, S.; Chiosis, G.; Taldone, T. Advances in the discovery and development of HSP90 inhibitors for cancer treatment. Expert Opin. Drug Dis. 2011, 6, 559-587.

  26. Taldone, T.; Gomes-DaGama, E. M.; Zong, H.; Sen, S.; Alpaugh, M. L.; Zatorska, D.; Alonso-Sabadell, R.; Guzman, M. L.; Chiosis, G. Synthesis of purine-scaffold fluorescent probes for heat shock protein 90 with use in flow cytometry and fluorescence microscopy. Bioorg. Med. Chem. Lett. 2011, 21, 5347-5352.

  27. Moulick, K.; Ahn, J. H.; Zong, H.; Rodina, A.; Cerchietti, L.; Gomes DaGama, E. M.; Caldas-Lopes, E.; Beebe, K.; Perna, F.; Hatzi, K.; Vu, L. P.; Zhao, X.; Zatorska, D.; Taldone, T.; Smith-Jones, P.; Alpaugh, M.; Gross, S. S.; Pillarsetty, N.; Ku, T.; Lewis, J. S.; Larson, S. M.; Levine, R.; Erdjument-Bromage, H.; Guzman, M. L.; Nimer, S. D.; Melnick, A.; Neckers, L.; Chiosis, G. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat. Chem. Biol. 2011, 7, 818-826.

  28. Taldone, T.; Zatorska, D.; Chiosis, G. Reaction of 2-Naphthylamine with Sodium Iodate/Sodium Sulfite: Synthesis of 2-Amino-1-iodonaphthalene. Synthetic Commun. 2012, 42, 635-638.

  29. Jhaveri, K.; Taldone, T.; Modi, S.; Chiosis, G. Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim. Biophys. Acta 2012, 1823, 742-755.

  30. Taldone, T.; Patel, P. D.; Patel, H. J.; Chiosis, G. About the reaction of aryl fluorides with sodium sulfide: investigation into the selectivity of substitution of fluorobenzonitriles to yield mercaptobenzonitriles via SNAr displacement of fluorine. Tetrahedron Lett. 2012, 53, 2548-2551.

  31. Taldone, T.; Zatorska, D.; Patel, H. J.; Sun, W.; Patel, M. R.; Chiosis, G. Preparation of a Diverse Purine-scaffold Library via One-step Palladium Catalyzed Cross-Coupling, Heterocycles 2013, 87, 91-113.

  32. Taldone, T.; Rodina, A.; Dagama Gomes, E. M.; Riolo, M.; Patel, H. J.; Alonso-Sabadell, R.; Zatorska, D.; Patel, M. R.; Kishinevsky, S.; Chiosis, G. Synthesis and evaluation of cell-permeable biotinylated PU-H71 derivatives as tumor Hsp90 probes. Beilstein J. Org. Chem. 2013, 9, 544-556.

  33. Amin, R. P.; Kunaparaju, N.; Kumar, S.; Taldone, T.; Barletta, M. A.; Zito, S. W. Structure elucidation and inhibitory effects on human platelet aggregation of chlorogenic acid from Wrightia tinctoria. J. Complement. Integr. Med. 2013, 10, 1-8.

  34. Beebe, K.; Mollapour, M.; Scroggins, B.; Prodromou, C.; Xu, W.; Tokita, M.; Taldone, T.; Pullen, L.; Zierer, B. K.; Lee, M. J.; Trepel, J.; Buchner, J.; Bolon, D.; Chiosis, G.; Neckers, L. Posttranslational modification and conformational state of Heat Shock Protein 90 differentially affect binding of chemically diverse small molecule inhibitors. Oncotarget 2013, 4, 1065-1074.

  35. Nayar, U.; Lu, P.; Goldstein, R. L.; Vider, J.; Ballon, G.; Rodina, A.; Taldone, T.; Erdjument-Bromage, H.; Chomet, M.; Blasberg, R.; Melnick, A.; Cerchietti, L.; Chiosis, G.; Wang, Y. L.; Cesarman, E. Blood 2013, 122, 2837-2847.

  36. Taldone, T.; Patel, D.; Patel, M.; Patel, H. J.; Evans, C. E.; Rodina, A.; Ochiana, S.; Shah, S. K.; Uddin, M.; Gewirth, D.; Chiosis, G. Experimental and structural testing module to analyze paralog-specificity and affinity in the Hsp90 inhibitors series. J. Med. Chem. 2013, 56, 6803-6818.

  37. Patel, P. D.; Yan, P.; Seidler, P. M.; Patel, H. J.; Sun, W.; Yang, C.; Que, N. S.; Taldone, T.; Finotti, P.; Stephani, R. A.; Gewirth, D. T.; Chiosis, G. Discovery of paralog specific Hsp90 inhibitors provides novel insights into tumor-specific regulation of an Hsp90 client protein. Nat. Chem. Biol. 2013, 9, 677-684.

  38. Shahinas, D.; Folefoc, A.; Taldone, T.; Chiosis, G.; Crandall, I.; Pillai, D. R. A Purine Analog Synergizes with Chloroquine (CQ) by Targeting Plasmodium falciparum Hsp90 (PfHsp90). PLoS One 2013, 8, e75446.

  39. Rodina, A; Patel, P. D.; Kang, Y.; Patel, Y.; Baaklini, I.; Wong, M. J.; 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.

  40. Miller, J. D.; Ganat, Y. M.; Kishinevsky, S.; Bowman, R. L.; Liu, B.; Tu, E. Y.; Mandal, P. K.; Vera, E.; Shim, J. W.; Kriks, S.; Taldone, T.; Fusaki, N.; Tomishima, M. J.; Krainc, D.; Milner, T. A.; Rossi, D. J.; Studer, L. Human iPSC-Based Modeling of Late-Onset Disease via Progerin-Induced Aging. Cell Stem Cell, 2013, 13, 691-705.

  41. Ambati, S. R.; Lopes, E. C.; Kosugi, K.; Mony, U.; Zehir, A.; Shah, S. K.; Taldone, T.; Moreira, A. L.; Meyers, P. A.; Chiosis, G.; Moore, M. A. Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma. Mol. Oncol. 2014, 8, 323-336.

  42. Bhagwat, N.; Koppikar, P.; Keller, M.; Marubayashi, S.; Shank, K.; Rampal, R.; Qi, J.; Kleppe, M.; Patel, H. J.; Shah, S. K.; Taldone, T.; Bradner, J. E.; Chiosis, G.; Levine, R. L. Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. Blood 2014, 123, 2075-2083.

  43. 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, 57, 1188-1207.

  44. 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. 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. J. Med. Chem. 2014, 57, 1208-1224.

  45. Taldone, T.; Patel, H. J.; Bolaender, A.; Patel, M. R.; Chiosis, G. Protein chaperones: a composition of matter review (2008 - 2013). Expert Opin. Ther. Pat. 2014, 24, 501-518.

  46. Rodina, A.; Taldone, T.; Kang, Y.; Patel, P. D.; Koren, J. 3rd; Yan, P.; DaGama Gomes, E. M.; Yang, C.; Patel, M. R.; Shrestha, L.; Ochiana, S. O.; Santarossa, C.; Maharaj, R.; Gozman, A.; Cox, M. B.; Erdjument-Bromage, H.; Hendrickson, R. C.; Cerchietti, L.; Melnick, A.; Guzman, M. L.; Chiosis, G. Affinity Purification Probes of Potential Use To Investigate the Endogenous Hsp70 Interactome in Cancer. ACS Chem. Biol. 2014, 9, 1698-1705.

  47. Taldone, T.; Ochiana, S. O.; Patel, P. D.; Chiosis, G. Selective targeting of the stress chaperome as a therapeutic strategy. Trends Pharmacol. Sci. 2014, 35, 592-603.

  48. Patel, H. J.; Patel, P. D.; Ochiana, S. O.; Yan, P.; Sun, W.; Patel, M.; Shah, S. K.; Tramentozzi, E.; Brooks, J.; Bolaender, A.; Shrestha, L.; Stephani, R. A.; Finotti, P.; Leifer, C.; Li, Z.; Gewirth, D. T.; Taldone, T.; Chiosis, G. Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog, Grp94. J. Med. Chem. 2015, 58, 3922−3943.

  49. Goldstein, R. L.; Yang, S. N.; Taldone, T.; Chang, B.; Gerecitano, J.; Elenitoba-Johnson, K.; Shaknovich, R.; Tam, W.; Leonard, J. P.; Chiosis, G.; Cerchietti, L.; Melnick, A. Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma. J. Clin. Invest. 2015, 125, 4559-4571.

  50. Culjkovic-Kraljacic, B.; Fernando, T. M.; Marullo, R.; Calvo-Vidal, N.; Verma, A.; Yang, S.; Tabbò, F.; Gaudiano, M.; Zahreddine, H.; Goldstein, R. L.; Patel, J.; Taldone, T.; Chiosis, G.; Ladetto, M.; Ghione, P.; Machiorlatti, R.; Elemento, O.; Inghirami, G.; Melnick, A.; Borden, K. L.; Cerchietti, L. Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas. Blood. 2016, 127, 858-868.

  51. Zong, H.; Gozman, A.; Caldas-Lopes, E.; Taldone, T.; Sturgill, E.; Brennan, S.; Ochiana, S. O.; Gomes-DaGama, E. M.; Sen, S.; Rodina, A.; Koren, J. 3rd; Becker, M. W.; Rudin, C. M.; Melnick, A.; Levine, R. L.; Roboz, G. J.; Nimer, S. D.; Chiosis, G.; Guzman, M. L. A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species. Cell Rep. 2015, 13, 2159-2173.

  52. Taldone, T.; Zatorska, D.; Ochiana, S. O.; Smith-Jones, P.; Koziorowski, J.; Dunphy, M. P.; Zanzonico, P.; Bolaender, A.; Lewis, J. S.; Larson, S. M.; Chiosis, G.; Pillarsetty, N. V. Radiosynthesis of the iodine-124 labeled Hsp90 inhibitor PU-H71. J. Labelled Comp. Radiopharm. 2016, 59, 129-132.

  53. Shrestha, L.; Bolaender, A.; Patel, H. J.; Taldone, T. Heat Shock Protein (HSP) Drug Discovery and Development: Targeting Heat Shock Proteins in Disease. Curr. Top. Med. Chem. 2016, 16, 2753-2764.

  54. Redelsperger, I. M.; Taldone, T.; Riedel, E. R.; Lepherd, M. L.; Lipman, N. S.; Wolf, F. R. Stability of Doxycycline in Feed and Water and Minimal Effective Doses in Tetracycline-Inducible Systems. J. Am. Assoc. Lab. Anim. Sci. 2016, 55, 467-474.

  55. Chung, S. Y.; Kishinevsky, S.; Mazzulli, J. R.; Graziotto, J.; Mrejeru, A.; Mosharov, E. V.; Puspita, L.; Valiulahi, P.; Sulzer, D.; Milner, T. A.; Taldone, T.; Krainc, D.; Studer, L.; Shim, J. W. Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation. Stem Cell Reports. 2016, 7, 664-677.

  56. Rodina, A.; Wang, T.; Yan, P.; Gomes, E. D.; Dunphy, M. P.; Pillarsetty, N.; Koren, J.; Gerecitano, J. F.; Taldone, T.; Zong, H.; Caldas-Lopes, E.; Alpaugh, M.; Corben, A.; Riolo, M.; Beattie, B.; Pressl, C.; Peter, R. I.; Xu, C.; Trondl, R.; Patel, H. J.; Shimizu, F.; Bolaender, A.; Yang, C.; Panchal, P.; Farooq, M. F.; Kishinevsky, S.; Modi, S.; Lin, O.; Chu, F.; Patil, S.; Erdjument-Bromage, H.; Zanzonico, P.; Hudis, C.; Studer, L.; Roboz, G. J.; Cesarman, E.; Cerchietti, L.; Levine, R.; Melnick, A.; Larson, S. M.; Lewis, J. S.; Guzman, M. L.; Chiosis, G. The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature. 2016, 538, 397-401.