550 West 120th Street, MC 4846
New York, NY 10027
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.
Yang WS, Stockwell BR. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol 2015 Nov [pubmed]
Shimada K, Stockwell BR. tRNA synthase suppression activates de novo cysteine synthesis to compensate for cystine and glutathione deprivation during ferroptosis. Mol Cell Onc 2015 Nov [pubmed]
Larraufie MH, Yang WS, Jiang E, Thomas AG, Slusher BS, Stockwell BR. Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility. Bioorg Med Chem Let 2015 Nov; 25(21):4787-92 [pubmed]
Stockwell BR, Stockwell MS, Cennamo M, Jiang E. Blended Learning Improves Science Education. Cell 2015 Aug; 162(5):933-6 [pubmed]
Kaplan A, Stockwell BR. Structural elucidation of a small molecule inhibitor of protein disulfide isomerase. ACS Med Chem Letters 2015 Jul; 6(9):966-971 [pubmed]
Hayano M, Yang WS, Corn CK, Pagano NC, and Stockwell Br. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ. 2015 Jul [pubmed]
Woo JH, Shimoni Y, Yang WS, Subramaniam P, Iyer A, Nicoletti P, Martinez MR, Lopez G, Mattioli M, Realubit R, Karan C, Stockwell BR, Bansal M, Califano A. Elucidating compound mechanism of action by network perturbation analysis. Cell 2015 Jul; 162(2):441-51 [pubmed]
Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, Superti-Furga G, Stockwell BR. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol 2015 Jul;10(7):1604-9 [pubmed]
Quartararo CE, Reznik E, deCarvalho AC, Mikkelson T, Stockwell BR High-throughput screening of patient-derived culture reveals potential for precision medicine in glioblastoma. ACS Med Chem Letters 2015 Jun; 6(8):948-52 [pubmed]
Kaplan A, Gaschler MG, Dunn DE, Colligan R, Brown LM, Palmer AG, Lo DC, Stockwell, BR. Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective. Proc Natl Acad Sci USA 2015 Apr; 112(17):E2245-52 [pubmed]
Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, Zen FD, Prokai A, Zuchtriegel G, Krombach F, Welz PS, Weinlich R, Berghe TV, Vandenabeele P, Pasparakis M, Bleich M, Weinberg JM, Reichel CA, Bräsen JH, Kunzendorf U, Anders HJ, Stockwell BR, Green DR, Krautwald S. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci USA2014 Nov; 111(47):16836-41 [pubmed]
Linkermann A, Stockwell BR, Krautwald S, Anders HJ. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat Rev Immunol. 2014 Nov; 14(11):759-67 [pubmed]
Julien O, Kampmann M, Bassik MC, Zorn JA, Venditto VJ, Shimbo K, Agard NJ, Shimada K, Rheingold AL, Stockwell BR, Weissman JS, Wells JA. Unraveling the mechanism of cell death induced by chemical fibrils. Nat Chem Biol. 2014 Sep 28; 10(11): 969-76 [pubmed]
Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, Alnemri ES, Altucci L, Andrews D, Annicchiarico-Petruzzelli M, Baehrecke EH, Bazan NG, Bertrand MJ, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Bredesen DE, Brenner C, Campanella M, Candi E, Cecconi F, Chan FK, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin KM, Di Daniele N, Dixit VM, Dynlacht BD, El-Deiry WS, Fimia GM, Flavell RA, Fulda S, Garrido C, Gougeon ML, Green DR, Gronemeyer H, Hajnoczky G, Hardwick JM, Hengartner MO, Ichijo H, Joseph B, Jost PJ, Kaufmann T, Kepp O, Klionsky DJ, Knight RA, Kumar S, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Lugli E, Madeo F, Malorni W, Marine JC, Martin SJ, Martinou JC, Medema JP, Meier P, Melino S, Mizushima N, Moll U, Muñoz-Pinedo C, Nuñez G, Oberst A, Panaretakis T, Penninger JM, Peter ME, Piacentini M, Pinton P, Prehn JH, Puthalakath H, Rabinovich GA, Ravichandran KS, Rizzuto R, Rodrigues CM, Rubinsztein DC, Rudel T, Shi Y, Simon HU, Stockwell BR, Szabadkai G, Tait SW, Tang HL, Tavernarakis N, Tsujimoto Y, Vanden Berghe T, Vandenabeele P, Villunger A, Wagner EF, Walczak H, White E, Wood WG, Yuan J, Zakeri Z, Zhivotovsky B, Melino G, Kroemer G. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 2014 Sep 19; 22(1):58-73 [pubmed]
Wolpaw AJ, Stockwell BR. Multidimensional profiling in the investigation of small-molecule-induced cell death. Methods Enzymol 2014 Jul; 545:265-302 [pubmed]
Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, Thomas AG, Gleason CE, Tatonetti N, Slusher BS, Stockwell BR. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 2014 May 20 [pubmed]
Cantley AM, Welsch ME, Ambesi-Impiombato A, Sanchez-Martin M, Kim MY, Bauer A, Ferrando A, Stockwell BR. Small Molecule that Reverses Dexamethasone Resistance in T-cell Acute Lymphoblastic Leukemia (T-ALL). ACS Med Chem Letters 2014 Apr 25;5(7):754-9 [pubmed]
Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, Rosenberg P, Lo D, Weinberg J, Linkermann A, Stockwell BR. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 2014 Mar 4; 136(12):4551-6 [pubmed]
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR. Regulation of Ferroptotic Cancer Cell Death by GPX4. Cell 2014 Jan 16; 156(1):317-331 [pubmed]
For a complete list of Publications, please visit the Stockwell Lab website.