Sloan-Kettering Institute // Molecular Pharmacology & Chemistry Program

Gabriela Chiosis, PhD

Research in my laboratory is aimed at developing pharmacologic tools that selectively target the pathogenic role of molecular chaperones; understanding how molecular chaperones effect their specialized roles in pathogenic cells; and creating a map of disease-specific molecular alterations, using selective chaperone modulators. Our laboratory operates at the interface of chemistry, biology, and medicine. Its research is focused on generating pharmacological and methodological tools for understanding the clinical relevance of modulating the function or expression of proteins involved in transformation (oncogenic and neurodegenerative) and in using these tools for the translation of agents into therapeutics. My group is interdisciplinary and functions with the understanding that we are able to discover and synthesize pharmacological agents, determine their mechanisms of action and significance in disease treatment, and ultimately develop rational strategies for their use in clinic.

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A chemical biology approach to investigate regulation of pathogenic stress by the molecular chaperone machinery

To allow for normal functioning, cells use intricate molecular machineries composed of thousands of proteins programmed to execute well-defined functions. Dysregulation in these pathways can lead to altered functions that confer a pathogenic cell phenotype. Although at the cellular level such dysregulation may be advantageous (i.e., increased survival in cancer), at the molecular level these changes occur at a cost to local energetic stability. To regain a pseudo-stable state, cells co-opt molecular chaperones to buffer molecular instability and allow the blossoming of the disease phenotype. It is becoming clearer that although the housekeeping roles of molecular chaperones have been revealed through genetic manipulations, their specialized roles in pathogenic transformation have evaded such recognition. It is through small molecules that we have learned of the intricate biological functions of Hsp90 in pathogenic cells. In this sense, molecular chaperones are beautiful examples of targets known and available for investigation through advances in chemical genetics. Many questions remain unanswered, and we are now positioned to approach these issues through pharmacologic agents and chemical tools developed or in development in our laboratory. We are also positioned to harvest the disease-specific buffering roles of chaperones into an understanding of the intricate global and detailed molecular lesions characteristic of each disease.

Publications

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

Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. 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. Nat Chem Biol. 2011 Sep 25;7(11):818-26. doi: 10.1038/nchembio.670.

Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS, Ma Y, Varticovski L, Melnick A, Chiosis G. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8368-73. doi: 10.1073/pnas.0903392106. Epub 2009 May 5.

Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Rodina A, Vilenchik M, Moulick K, Aguirre J, Kim J, Chiang A, Litz J, Clement CC, Kang Y, She Y, Wu N, Felts S, Wipf P, Massague J, Jiang X, Brodsky JL, Krystal GW, Chiosis G. Nat Chem Biol. 2007 Aug;3(8):498-507. Epub 2007 Jul 1.

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