We are using chemical tools to define the interconnected signaling networks underlying cancer and neurodegeneration. Our approach is to perform high-throughput screens with small organic molecules to identify compounds and proteins that act as critical regulators of disease processes. We then define the molecular functions of these critical regulators using the tools of chemical synthesis, protein biochemistry and molecular cell biology.
In this “chemical genetic” approach, small organic molecules that bind directly to proteins are used to alter protein function. This unbiased, discovery-based strategy enables the dissection of signaling pathways in mammalian cells, which are otherwise not amenable to such systematic genetic-like analyses. Potential research projects include synthesizing chemical libraries, identifying the protein targets of novel compounds we have discovered, developing and executing high-throughput assays, creating novel photoaffinity reagents and fluorescent sensors and defining protein ligation events associated with disease proteins.
Our approach to understanding the function of oncoproteins uses synthetic lethal screens to identify small molecules that selectively kill tumor cells expressing specific oncoproteins. Such selectively lethal compounds can target the designated oncoprotein itself, or other proteins in an oncoprotein-linked signaling network. We recently described a novel compound, derived from a combinatorial library, that selectively kills tumorigenic cells expressing both the RASV12 and Small T (ST) oncoproteins. We observed that this new compound, which we named erastin, kills tumorigenic cells without activating apoptosis, which is surprising given the fact that most antitumor agents act by initiating apoptosis. We seek to define the mode of cell death initiated by erastin and the specific proteins that erastin interacts with.
We are also developing new collections of small molecules; for example, via the synthesis of small-molecule inhibitors of E3 ubiquitin ligases, which are components of the ubiquitin-degradation pathway, and determining whether such inhibitors restore tumor suppressor levels and functions in cancer cells. This strategy will provide a framework from which to develop small molecule inhibitors of many critical E3 ubiquitin ligases with relevance to cancer and neurodegeneration.
Finally, we are creating new fluorescent sensors to monitor protein modification events in cells. Such modifications include the covalent coupling of small ubiquitin-like proteins (UBLs) to larger target proteins via specific enzymes. We are developing a series of UBL-derived fluorescent, photoaffinity reagents that will enable determination of protein ligation events that occur on disease-related proteins. These probes will define the role of specific protein ligation events in oncogenic and neurodegenerative processes.
Wolpaw AJ, Shimada K, Skouta R, Welsch ME, Akavia UD, Pe’er D, Shaik F, Bulinski JC and Stockwell BR.Modulatory Profiling Identifies Mechanisms of Small Molecule-Induced Cell Death. Proc Natl Acad Sci USA 2011 Aug.
Herman AG, Hayano M, Poyurovsky MV, Shimada K, Skouta R, Prives C and Stockwell BR. Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay. Cancer Discovery 2011 Jul.
Bauer AJ, Gieschler S, Lemberg KM, McDermott AE, Stockwell BR. Functional Model of Metabolite Gating by Human Voltage-Dependent Anion Channel 2. Biochemistry 2011 Apr.
Hoffstrom BG, Kaplan A, Letso R, Schmid RS, Turmel GJ, Lo DC, Stockwell BR. Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins. Nat Chem Biol2010 Dec.
Varma H, Yamamoto A, Sarantos MR, Hughes RE, Stockwell BR. Mutant Huntingtin Alters Cell Fate in Response to Microtubule Depolymerization via GEF-H1-RhoA-ERK Pathway. J Biol Chem2010 Sep.
Cancer Target Discovery and Development Network, Schreiber SL, Shamji AF, Clemons PA, Hon C, Koehler AN, Munoz B, Palmer M, Stern AM, Wagner BK, Powers S, Lowe SW, Guo X, Krasnitz A, Sawey ET, Sordella R, Stein L, Trotman LC, Califano A, Dalla-Favera R, Ferrando A, Iavarone A, Pasqualucci L, Silva J, Stockwell BR, Hahn WC, Chin L, DePinho RA, Boehm JS, Gopal S, Huang A, Root DE, Weir BA, Gerhard DS, Zenklusen JC, Roth MG, White MA, Minna JD, MacMillan JB, Posner BA. Towards patient-based cancer therapeutics. Nat Biotech 2010 Sep;28(9):904-6.
Welsch ME, Snyder SA, Stockwell BR. Privileged scaffolds for library design and drug discovery. Curr Opin Chem Biol 2010 Jun;14(3):347-361.
Dixon SJ, Stockwell BR. Drug discovery: Engineering drug combinations. Nat Chem Biol 2010 May;6(5):318-319.
“Identifying druggable disease-modifying gene products” S. J. Dixon, B. R Stockwell, Curr. Opin. Cell Biol. 13:1-7 (2009)
“Combination ghemical genetics” J. Lehar, B. R. Stockwell, G. Giaever G, C. Nislow, W. S. Yang, B. R. Stockwell, Nat. Biol. Chem. 4:674-81 (2008)
“Gene expression-based screening for inhibitors of PDGFR signaling” A. A. Antipova, B. R. Stockwell, T. R. Golub Genome Biol. 9: R47 (2008)
“High throughput screening for neurodegeneration and complex disease phenotypes” H. Varma, D. C. Lo, B. R. Stockwell, Comb Chem High Throughput Screen 3:238-48 (2008)
“A novel role for jun N-terminal kinase signaling in olfactory sensory neuronal death” N. M. Gangadhar, S.J. Firestein, B. R. Stockwell, Mol. Cell Neurosci. 38(4):518-25 (2008)
“Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer Cells” W. S. Yang, B. R. Stockwell. Chem Biol. 3:234-45 (2008)
“Chemical combination effects predict connectivity in biological systems” J. Lehar, G. R. Zimmermann, A. S. Krueger, R. A. Molnar, J. T. Ledell, A. M. Heilbut, G. F. Short 3rd, L. C. Giust, G. P. Nolan, O. A. Magid, M. S. Lee, A. A. Borisy, B. R. Stockwell, C. T. Keith, Molecular Systems Biology 3:80 (2007)
“Identification of potential therapeutic drugs for huntington’s disease using Caenorhabditis elegans” C. Voisine, H. Varma, N. Walker, E. A. Bates, B. R. Stockwell, A. C. Hart, PLOS One 2:e504 (2007)
“Inhibitors of metabolism rescue cell death in Huntington’s disease models” H. Varma, R. Cheng, C. Voisine, A. C. Hart, B. R. Stockwell, PNAS 104:14525-30 (2007)
“RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels” N. Yagoda, M. von Rechenberg, E. Zaganjor, A. J. Bauer, W. S. Yang, D. J. Fridman, A. J. Wolpaw, I. Smukste, J. M. Peltier, J. J. Boniface, R. Smith, S. L. Lessnick, S. Sahasrabudhe, B. R. Stockwell, Nature 447:864-8 (2007)