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Development of Chemical Tools and Assays

Chemical tools address the biology of proteins in the cellular environment where the protein is limiting but not absent and can probe and manipulate a protein’s function in a controlled manner. Such a molecular toolkit comprises ligands, labeled inhibitors, and solid-support immobilized inhibitors that are developed with a biological application in mind. For example these can be modulated to be cell permeable or impermeable, targeted to specific cellular compartments, or tailored to be useful for a specific investigation.

As research aids, chemical tools have the potential to extend the study of single targets to a particular class of molecules or even to an entire proteome. In addition, the development of powerful chemical tools designed to probe or modulate the activity of biomolecules in live biological systems can lay the foundation for a type of “live biochemistry and biology.” Such studies can complement traditional, genetic, biochemical, and biological approaches by aiding the molecular characterization of biomolecules both in vitro and within their natural biological contexts.

Together with medicinal chemistry, which provides the know-how to adjust these chemical tools to have the characteristics necessary for in vivo studies (i.e., favorable bioavailability and toxicology, proper in vivo target modulation), these two strategies promise to offer important insights into the function and regulation of the molecules that regulate life processes and, in turn, facilitate development of new therapeutics for the treatment of diseases.

Patel PD, Yan P, Seidler PM, Patel HJ, Sun W, Yang C, Que NS, Taldone T, Finotti P, Stephani RA, Gewirth DT, Chiosis G. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Biol. 2013 Sep 1. doi: 10.1038/nchembio.1335. [Epub ahead of print]

Taldone T, Patel PD, Patel M, Patel HJ, Evans CE, Rodina A, Ochiana S, Shah SK, Uddin M, Gewirth D, Chiosis G. Experimental and Structural Testing Module to Analyze Paralogue-Specificity and Affinity in the Hsp90 Inhibitors Series. J Med Chem. 2013 Aug 21. [Epub ahead of print]

Taldone T, Rodina A, Gomes-DaGama  EM, Riolo M, Patel HJ, Alonso-Sabadell R, Zatorska D, Patel MR, Kishinevsky S, Chiosis G. Synthesis and evaluation of cell-permeable biotinylated PU-H71 derivatives as tumor Hsp90 probes. Beilstein J Org Chem. 2013 Mar 15;9:544-56. doi: 10.3762/bjoc.9.60. Print 2013.

Janjigian YY, Viola-Villegas N, Holland JP, Divilov V, Carlin SD, Gomes-DaGama EM, Chiosis G, Carbonetti G, de Stanchina E, Lewis JS. Monitoring afatinib treatment in HER2-positive gastric cancer with 18F-FDG and 89Zr-trastuzumab PET. J Nucl Med. 2013 Jun;54(6):936-43. doi: 10.2967/jnumed.112.110239. Epub 2013 Apr 11.

Chan CT, Reeves RE, Geller R, Yaghoubi SS, Hoehne A, Solow-Cordero DE, Chiosis G, Massoud TF, Paulmurugan R, Gambhir SS. Discovery and validation of small-molecule heat-shock protein 90 inhibitors through multimodality molecular imaging in living subjects. Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):E2476-85. doi: 10.1073/pnas.1205459109. Epub 2012 Aug 15.

Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes-DaGama EM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G. Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol. 2011 Sep 25;7(11):818-26. doi: 10.1038/nchembio.670.

Taldone T, Gomes-DaGama EM, Zong H, Sen S, Alpaugh ML, Zatorska D, Alonso-Sabadell R, Guzman ML, 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 Sep 15;21(18):5347-52. doi: 10.1016/j.bmcl.2011.07.026. Epub 2011 Jul 14.

Taldone T, Zatorska D, Patel PD, Zong H, Rodina A, Ahn JH, Moulick K, Guzman ML, Chiosis G. Design, synthesis, and evaluation of small molecule Hsp90 probes. Bioorg Med Chem. 2011 Apr 15;19(8):2603-14. doi: 10.1016/j.bmc.2011.03.013. Epub 2011 Mar 12. Review.

Ahn JH, Luo W, Kim J, Rodina A, Clement CC, Aguirre J, Sun W, Kang Y, Maharaj R, Moulick K, Zatorska D, Kokoszka M, Brodsky JL, Chiosis G. Design of a flexible cell-based assay for the evaluation of heat shock protein 70 expression modulators. Assay Drug Dev Technol. 2011 Jun;9(3):236-46. doi: 10.1089/adt.2010.0327. Epub 2010 Dec 6.

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 Negl Trop Dis. 2010 Jun 15;4(6):e714. doi: 10.1371/journal.pntd.0000714.

Holland JP, Caldas-Lopes E, Divilov V, Longo VA, Taldone T, Zatorska D, Chiosis G, Lewis JS. Measuring the pharmacodynamic effects of a novel Hsp90 inhibitor on HER2/neu expression in mice using Zr-DFO-trastuzumab. PLoS One. 2010 Jan 25;5(1):e8859. doi: 10.1371/journal.pone.0008859.

Chiosis G, Keeton AB. Assay for isolation of inhibitors of her2-kinase expression. Methods Mol Biol. 2009;486:139-49. doi: 10.1007/978-1-60327-545-3_10.

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 Jan 15;19(2):415-7.doi: 10.1016/j.bmcl.2008.11.057. Epub 2008 Nov 20.

Taldone T, Sun W, Chiosis G. Discovery and development of heat shock protein 90 inhibitors. Bioorg Med Chem. 2009 Mar 15;17(6):2225-35. doi:10.1016/j.bmc.2008.10.087. Epub 2008 Nov 6. Review.

Kang Y, Taldone T, Clement CC, Fewell SW, Aguirre J, Brodsky JL, Chiosis G. Design of a fluorescence polarization assay platform for the study of human Hsp70. Bioorg Med Chem Lett. 2008 Jul 1;18(13):3749-51. doi:10.1016/j.bmcl.2008.05.046. Epub 2008 May 16.

Chan CT, Paulmurugan R, Gheysens OS, Kim J, Chiosis G, Gambhir SS. Molecular imaging of the efficacy of heat shock protein 90 inhibitors in living subjects. Cancer Res. 2008 Jan 1;68(1):216-26. doi: 10.1158/0008-5472.CAN-07-2268.

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 Screen. 2007 Oct;12(7):915-24.

Immormino RM, Kang Y, Chiosis G, Gewirth DT. Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors. J Med Chem. 2006 Aug 10;49(16):4953-60.

Moulick K, Clement CC, Aguirre J, Kim J, Kang Y, Felts S, Chiosis G. Synthesis of a red-shifted fluorescence polarization probe for Hsp90. Bioorg Med Chem Lett. 2006 Sep 1;16(17):4515-8. Epub 2006 Jun 22.

Chiosis G, Aguirre J, Nicchitta CV. Synthesis of Hsp90 dimerization modulators. Bioorg Med Chem Lett. 2006 Jul 1;16(13):3529-32. Epub 2006 Apr 18.

He H, Zatorska D, Kim J, Aguirre J, Llauger L, She Y, Wu N, Immormino RM, Gewirth DT, Chiosis G. Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90. J Med Chem. 2006 Jan 12;49(1):381-90.

Llauger L, He H, Kim J, Aguirre J, Rosen N, Peters U, Davies P, Chiosis G. Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90. J Med Chem. 2005 Apr 21;48(8):2892-905.

Kim J, Felts S, Llauger L, He H, Huezo H, Rosen N, Chiosis G. Development of a fluorescence polarization assay for the molecular chaperone Hsp90. J Biomol Screen. 2004 Aug;9(5):375-81.

He H, Llauger L, Rosen N, Chiosis G. General method for the synthesis of 8-arylsulfanyl adenine derivatives. J Org Chem. 2004 Apr 30;69(9):3230-2.

Llauger-Bufi L, Felts SJ, Huezo H, Rosen N, Chiosis G. Synthesis of novel fluorescent probes for the molecular chaperone Hsp90. Bioorg Med Chem Lett. 2003 Nov 17;13(22):3975-8.

Huezo H, Vilenchik M, Rosen N, Chiosis G. Microtiter cell-based assay for detection of agents that alter cellular levels of Her2 and EGFR. Chem Biol. 2003 Jul;10(7):629-34.

Yamamoto K, Garbaccio RM, Stachel SJ, Solit DB, Chiosis G, Rosen N, Danishefsky SJ. Total synthesis as a resource in the discovery of potentially valuable antitumor agents: cycloproparadicicol. Angew Chem Int Ed Engl. 2003 Mar 17;42(11):1280-4.

Chiosis G, Lucas B, Shtil A, Huezo H, Rosen N. Development of a purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of Her2 tyrosine kinase. Bioorg Med Chem. 2002 Nov;10(11):3555-64.

Lucas B, Rosen N, Chiosis G. Facile synthesis of a library of 9-alkyl-8-benzyl-9H-purin-6-ylamine derivatives. J Comb Chem. 2001 Nov-Dec;3(6):518-20.

Chiosis G, Timaul MN, Lucas B, Munster PN, Zheng FF, Sepp-Lorenzino L, Rosen N. A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells. Chem Biol. 2001 Mar;8(3):289-99.

Chiosis G, Rosen N, Sepp-Lorenzino L. LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related family. Bioorg Med Chem Lett. 2001 Apr 9;11(7):909-13.

Zheng FF, Kuduk SD, Chiosis G, Münster PN, Sepp-Lorenzino L, Danishefsky SJ, Rosen N. Identification of a geldanamycin dimer that induces the selective degradation of HER-family tyrosine kinases. Cancer Res. 2000 Apr 15;60(8):2090-4.