Ambystoma mexicanum; Biochemistry; Biology; Chemistry; Cell Biology; Neoplasms; Pharmacology; Regeneration; Drugs, Investigational; Developmental Biology; Proteasome Endopeptidase Complex; Proteasome Inhibitors
Postnatal Development & Regeneration
Stem Cell Center, Yale: Stem Cells and Tissue Repair
We use a combination of biochemistry, molecular biology, and bio-organic chemistry to explore different aspects of developmental and cell biology. Different projects include 1) the exploration of how biologically active compounds from nature work in order to identify new probes for cell biology as well as identify novel drug targets and 2) the development of novel small molecules to control intracellular protein homeostasis.
Extensive Research Description
We develop novel reagents, which will allow us to explore new areas in cell biology. This 'chemical genetic' approach uses biologically active natural products and de novo designed small molecules to identify critical components in intracellular processes. In the past few years, our efforts have focused on anti-angiogenic, antitumor and anti-inflammatory natural products. More recently, we have explored the use of small molecules to control intracellular protein levels, either by inhibiting their degradation or by inducing their proteolysis via the 26S proteasome. A goal of this research is to develop novel methodologies that would allow for small molecule control of the 'undruggable proteome'.
- Toure, M, and Crews CM (2016) All "Small Molecule" PROTACS: New Members of a Degrading Family. Angewandte Chemie Int. Ed. Engl 55(6):2-10
- Lai, AC, Toure, M, Hellerschmied, D, Salami, J, Jaime-Figueroa, S, Ko, E, Hines, J, Crews, CM (2015) Accessing Oncogenic BCR-ABL for Degradation by Modular PROTAC Design. Angewandte Chemie Int. Ed. Engl. 55: 807–810
- Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Himes J, Winkler JD, Crew AP, Coleman K, Crews CM (2015) Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chemistry & Biology 22: 1-9
- Bondeson DP, Mares A, Smith IED, Ko E, Campos S, Miah AH, Mulholland KE, Routly N, Buckley DL, Gustafson JL, Zinn N, Grandi P, Shimamura S, Bergamini G, Faelth-Savitski M, Bantscheff M, Cox C, Gordon DA, Willard RR, Flanagan JJ, Casillas LN, Votta BJ, den Besten W, Famm K, Sruidenier L, Carter PS, Harling JD, Churcher I, & Crews CM (2015) Catalytic in vivo protein knockdown by small-molecule PROTACs. Nature Chemical Biology. 2015 Aug;11(8):611-7.
- Gustafson JL, Neklesa TK, Cox CS, Roth AG, Buckley DL, Tae HS, Sundberg TB, Stagg B, Hines J, McDonnell DP, Norris JD, Crews CM. (2015) Small-Molecule-Mediated Degradation of the Androgen Receptor Through Hydrophobic Tagging. Angewandte Chemie Int. Ed. Engl. 10;54(33):9659-62
- Hines J, Gough JD, Corson TW, Crews CM. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proc Natl Acad Sci U S A. (2013), May 28; 110(22):8942-7.
- Neklesa TK, Crews CM. Chemical biology: Greasy tags for protein removal. Nature. (2012) Jul 18;487(7407):308-9.
- Neklesa TK, Tae H-S, Schneekloth AR, Stulberg MJ, Corson TW, Sundberg TB, Holley SA, and CM Crews. (2011) Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nature Chemical Biology, 7(8):538-43
- Raina K and CM Crews. (2010) Chemical Inducers of Targeted Protein Degradation. J. Biol. Chem, 285(15):11057-60.
- Kim KB, Crews CM. (2013) From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes. Nat Prod Rep. 30(5):600-4.
- Neklesa TK, Noblin DJ, Kuzin AP , Lew S, Seetharaman J, Acton TB, Kornhaber GJ, Xiao R, Montelione GT, Tong L, Crews CM. (2013) A Bidirectional System for the Dynamic Small Molecule Control of Intracellular Fusion Proteins. ACS Chemical Biology 8(10);2293-2300.
- Buckley DL, and Crews CM. (2014) Small Molecule Control of Intracellular Protein Levels Through Modulation of the Ubiquitin Proteasome System. Angewandte Chem. Int. Ed. 53(9);2312-2330.
- Raina K, Noblin DJ, Serebrenik YV, Adams A, Zhao C, Crews CM. (2014) Targeted Protein Destabilization Reveals an Estrogen-mediated ER Stress Response. Nature Chemical Biology, 10(11):957-962.
- Buckley DL, Raina K, Darricarrerre N, Hines J, Gustafson JL, Smith IE, Miah AH, Harling JD, Crews CM. (2015) HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins. ACS Chem. Biol. 10(8):1831-7
- Molineaux, C, and CM Crews. (2008) Proteasome Inhibitors in Cancer Chemotherapy, Cancer: Principles and Practice of Oncology, 8th Ed. V.T DeVita, T.S. Lawrence, S.A. Rosenberg, editors. Chapter 25., pp.486-490.
- Flowers GP, Timberlake AT, Mclean KC, Monaghan JR, Crews CM. (2014) Highly Efficient Targeted Mutagenesis in the Axolotl using Cas9 RNA-guided Nuclease. Development, 141(10):2165-71.
- Crews CM. (2010) Targeting the Undruggable Proteome: The Small Molecules of My Dreams. Chemistry & Biology, 17:551-555.