Craig Crews, PhD
John C. Malone Professor of Molecular, Cellular, and Developmental Biology and Professor of Chemistry, of Pharmacology, and of Management; Executive Director, Yale Center for Molecular Discovery
Research & Publications
Biography
News
Research Summary
We use a combination of biochemistry, molecular biology, and bio-organic chemistry to explore different aspects of developmental and cell biology. Different projects include the development of novel small molecules to control intracellular processes such as protein homeostasis and signal transduction.
Extensive Research Description
We develop novel reagents and methodologies, which will allow us to explore new areas in cell biology. This 'chemical genetic' approach uses biologically active small molecules to control various intracellular processes. For example we developed the PROTAC technology that decrease target protein levels within cells 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'.
Research Interests
Biochemistry; Biology; Chemistry; Cell Biology; Neoplasms; Pharmacology; Drugs, Investigational; Proteasome Endopeptidase Complex; Proteasome Inhibitors
Research Image
PROTACs: Induced Protein Degradation as a New Pharmaceutical Paradigm
Since 2000, the Crews lab has focused on developing new methodologies for "Controlled Proteostasis" such as Proteolysis Targeting Chimeras (PROTACs), which are powerful inducers of protein degradation that remove unwanted proteins from cells.
Selected Publications
- Induced protein degradation: an emerging drug discovery paradigm.Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nature Reviews. Drug Discovery 2017, 16:101-114.
- Small-Molecule PROTACS: New Approaches to Protein Degradation.Toure M, Crews CM. Small-Molecule PROTACS: New Approaches to Protein Degradation. Angewandte Chemie (International Ed. In English) 2016, 55:1966-73.
- Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL.Lai AC, Toure M, Hellerschmied D, Salami J, Jaime-Figueroa S, Ko E, Hines J, Crews CM. Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL. Angewandte Chemie (International Ed. In English) 2016, 55:807-10.
- Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4.Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K, Crews CM. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chemistry & Biology 2015, 22:755-63.
- Catalytic in vivo protein knockdown by small-molecule PROTACs.Bondeson DP, Mares A, Smith IE, 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, Kruidenier L, Carter PS, Harling JD, Churcher I, Crews CM. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nature Chemical Biology 2015, 11:611-7.
- Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging.Gustafson JL, Neklesa TK, Cox CS, Roth AG, Buckley DL, Tae HS, Sundberg TB, Stagg DB, Hines J, McDonnell DP, Norris JD, Crews CM. Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging. Angewandte Chemie (International Ed. In English) 2015, 54:9659-62.
- Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs.Hines J, Gough JD, Corson TW, Crews CM. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110:8942-7.
- Chemical biology: Greasy tags for protein removal.Neklesa TK, Crews CM. Chemical biology: Greasy tags for protein removal. Nature 2012, 487:308-9.
- Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins.Neklesa TK, Tae HS, Schneekloth AR, Stulberg MJ, Corson TW, Sundberg TB, Raina K, Holley SA, Crews CM. Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nature Chemical Biology 2011, 7:538-43.
- Chemical inducers of targeted protein degradation.Raina K, Crews CM. Chemical inducers of targeted protein degradation. The Journal Of Biological Chemistry 2010, 285:11057-60.
- From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes.Kim KB, Crews CM. From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes. Natural Product Reports 2013, 30:600-4.
- A bidirectional system for the dynamic small molecule control of intracellular fusion proteins.Neklesa TK, Noblin DJ, Kuzin A, Lew S, Seetharaman J, Acton TB, Kornhaber G, Xiao R, Montelione GT, Tong L, Crews CM. A bidirectional system for the dynamic small molecule control of intracellular fusion proteins. ACS Chemical Biology 2013, 8:2293-2300.
- Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system.Buckley DL, Crews CM. Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system. Angewandte Chemie (International Ed. In English) 2014, 53:2312-30.
- Targeted protein destabilization reveals an estrogen-mediated ER stress response.Raina K, Noblin DJ, Serebrenik YV, Adams A, Zhao C, Crews CM. Targeted protein destabilization reveals an estrogen-mediated ER stress response. Nature Chemical Biology 2014, 10:957-62.
- HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins.Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL, Smith IE, Miah AH, Harling JD, Crews CM. HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins. ACS Chemical Biology 2015, 10:1831-7.
- Highly efficient targeted mutagenesis in axolotl using Cas9 RNA-guided nuclease.Flowers GP, Timberlake AT, McLean KC, Monaghan JR, Crews CM. Highly efficient targeted mutagenesis in axolotl using Cas9 RNA-guided nuclease. Development (Cambridge, England) 2014, 141:2165-71.
- Targeting the undruggable proteome: the small molecules of my dreams.Crews CM. Targeting the undruggable proteome: the small molecules of my dreams. Chemistry & Biology 2010, 17:551-5.
- Interleukin 2 stimulation of p70 S6 kinase activity is inhibited by the immunosuppressant rapamycin.Calvo V, Crews CM, Vik TA, Bierer BE. Interleukin 2 stimulation of p70 S6 kinase activity is inhibited by the immunosuppressant rapamycin. Proceedings Of The National Academy Of Sciences Of The United States Of America 1992, 89:7571-5.
- Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product.Crews CM, Erikson RL. Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product. Proceedings Of The National Academy Of Sciences Of The United States Of America 1992, 89:8205-9.
- The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product.Crews CM, Alessandrini A, Erikson RL. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science (New York, N.Y.) 1992, 258:478-80.
- Erks: their fifteen minutes has arrived.Crews CM, Alessandrini A, Erikson RL. Erks: their fifteen minutes has arrived. Cell Growth & Differentiation : The Molecular Biology Journal Of The American Association For Cancer Research 1992, 3:135-42.
- Phorbol ester stimulates a protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product.Alessandrini A, Crews CM, Erikson RL. Phorbol ester stimulates a protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product. Proceedings Of The National Academy Of Sciences Of The United States Of America 1992, 89:8200-4.
- Mouse Erk-1 gene product is a serine/threonine protein kinase that has the potential to phosphorylate tyrosine.Crews CM, Alessandrini AA, Erikson RL. Mouse Erk-1 gene product is a serine/threonine protein kinase that has the potential to phosphorylate tyrosine. Proceedings Of The National Academy Of Sciences Of The United States Of America 1991, 88:8845-9.
- Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase.Alcorta DA, Crews CM, Sweet LJ, Bankston L, Jones SW, Erikson RL. Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase. Molecular And Cellular Biology 1989, 9:3850-9.
- GTP-dependent binding of the antiproliferative agent didemnin to elongation factor 1 alpha.Crews CM, Collins JL, Lane WS, Snapper ML, Schreiber SL. GTP-dependent binding of the antiproliferative agent didemnin to elongation factor 1 alpha. The Journal Of Biological Chemistry 1994, 269:15411-4.
- Raf-1 forms a stable complex with Mek1 and activates Mek1 by serine phosphorylation.Huang W, Alessandrini A, Crews CM, Erikson RL. Raf-1 forms a stable complex with Mek1 and activates Mek1 by serine phosphorylation. Proceedings Of The National Academy Of Sciences Of The United States Of America 1993, 90:10947-51.
- MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues.Brott BK, Alessandrini A, Largaespada DA, Copeland NG, Jenkins NA, Crews CM, Erikson RL. MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues. Cell Growth & Differentiation : The Molecular Biology Journal Of The American Association For Cancer Research 1993, 4:921-9.
- Extracellular signals and reversible protein phosphorylation: what to Mek of it all.Crews CM, Erikson RL. Extracellular signals and reversible protein phosphorylation: what to Mek of it all. Cell 1993, 74:215-7.
- Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro.Macdonald SG, Crews CM, Wu L, Driller J, Clark R, Erikson RL, McCormick F. Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro. Molecular And Cellular Biology 1993, 13:6615-20.
- The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2.Sin N, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94:6099-103.
- The antiproliferative agent didemnin B uncompetitively inhibits palmitoyl protein thioesterase.Meng L, Sin N, Crews CM. The antiproliferative agent didemnin B uncompetitively inhibits palmitoyl protein thioesterase. Biochemistry 1998, 37:10488-92.
- Eponemycin analogues: syntheses and use as probes of angiogenesis.Sin N, Meng L, Auth H, Crews CM. Eponemycin analogues: syntheses and use as probes of angiogenesis. Bioorganic & Medicinal Chemistry 1998, 6:1209-17.
- Structure of human methionine aminopeptidase-2 complexed with fumagillin.Liu S, Widom J, Kemp CW, Crews CM, Clardy J. Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science (New York, N.Y.) 1998, 282:1324-7.
- Eponemycin exerts its antitumor effect through the inhibition of proteasome function.Meng L, Kwok BH, Sin N, Crews CM. Eponemycin exerts its antitumor effect through the inhibition of proteasome function. Cancer Research 1999, 59:2798-801.
- Total synthesis of the potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology.Sin N, Kim KB, Elofsson M, Meng L, Auth H, Kwok BH, Crews CM. Total synthesis of the potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology. Bioorganic & Medicinal Chemistry Letters 1999, 9:2283-8.
- Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity.Meng L, Mohan R, Kwok BH, Elofsson M, Sin N, Crews CM. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96:10403-8.
- Towards subunit-specific proteasome inhibitors: synthesis and evaluation of peptide alpha',beta'-epoxyketones.Elofsson M, Splittgerber U, Myung J, Mohan R, Crews CM. Towards subunit-specific proteasome inhibitors: synthesis and evaluation of peptide alpha',beta'-epoxyketones. Chemistry & Biology 1999, 6:811-22.
- Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: insights into specificity and potency.Kim KB, Myung J, Sin N, Crews CM. Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: insights into specificity and potency. Bioorganic & Medicinal Chemistry Letters 1999, 9:3335-40.
- The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses.Schwarz K, de Giuli R, Schmidtke G, Kostka S, van den Broek M, Kim KB, Crews CM, Kraft R, Groettrup M. The selective proteasome inhibitors lactacystin and epoxomicin can be used to either up- or down-regulate antigen presentation at nontoxic doses. Journal Of Immunology (Baltimore, Md. : 1950) 2000, 164:6147-57.
- The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest.Yeh JR, Mohan R, Crews CM. The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97:12782-7.
- Cells adapted to the proteasome inhibitor 4-hydroxy- 5-iodo-3-nitrophenylacetyl-Leu-Leu-leucinal-vinyl sulfone require enzymatically active proteasomes for continued survival.Princiotta MF, Schubert U, Chen W, Bennink JR, Myung J, Crews CM, Yewdell JW. Cells adapted to the proteasome inhibitor 4-hydroxy- 5-iodo-3-nitrophenylacetyl-Leu-Leu-leucinal-vinyl sulfone require enzymatically active proteasomes for continued survival. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98:513-8.
- Lack of proteasome active site allostery as revealed by subunit-specific inhibitors.Myung J, Kim KB, Lindsten K, Dantuma NP, Crews CM. Lack of proteasome active site allostery as revealed by subunit-specific inhibitors. Molecular Cell 2001, 7:411-20.
- The ubiquitin-proteasome pathway and proteasome inhibitors.Myung J, Kim KB, Crews CM. The ubiquitin-proteasome pathway and proteasome inhibitors. Medicinal Research Reviews 2001, 21:245-73.
- Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98:8554-9.
- The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase.Kwok BH, Koh B, Ndubuisi MI, Elofsson M, Crews CM. The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chemistry & Biology 2001, 8:759-66.
- Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro.Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G, Harris SE, Gallwitz W, Kim KB, Hu S, Crews CM, Mundy GR. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. The Journal Of Clinical Investigation 2003, 111:1771-82.
- Probing protein function with small molecules.Gough JD, Crews CM. Probing protein function with small molecules. Ernst Schering Research Foundation Workshop 2006, 61-74.
- Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer.Rodriguez-Gonzalez A, Cyrus K, Salcius M, Kim K, Crews CM, Deshaies RJ, Sakamoto KM. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene 2008, 27:7201-11.
- Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.Saenz DT, Fiskus W, Qian Y, Manshouri T, Rajapakshe K, Raina K, Coleman KG, Crew AP, Shen A, Mill CP, Sun B, Qiu P, Kadia TM, Pemmaraju N, DiNardo C, Kim MS, Nowak AJ, Coarfa C, Crews CM, Verstovsek S, Bhalla KN. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia 2017, 31:1951-1961.
- BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells.Sun B, Fiskus W, Qian Y, Rajapakshe K, Raina K, Coleman KG, Crew AP, Shen A, Saenz DT, Mill CP, Nowak AJ, Jain N, Zhang L, Wang M, Khoury JD, Coarfa C, Crews CM, Bhalla KN. BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. Leukemia 2018, 32:343-352.
- Mutant-selective degradation by BRAF-targeting PROTACs.Alabi S, Jaime-Figueroa S, Yao Z, Gao Y, Hines J, Samarasinghe KTG, Vogt L, Rosen N, Crews CM. Mutant-selective degradation by BRAF-targeting PROTACs. Nature Communications 2021, 12:920.
- BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma.Fiskus W, Mill CP, Perera D, Birdwell C, Deng Q, Yang H, Lara BH, Jain N, Burger J, Ferrajoli A, Davis JA, Saenz DT, Jin W, Coarfa C, Crews CM, Green MR, Khoury JD, Bhalla KN. BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma. Leukemia 2021, 35:2621-2634.
- Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras.Samarasinghe KTG, Jaime-Figueroa S, Burgess M, Nalawansha DA, Dai K, Hu Z, Bebenek A, Holley SA, Crews CM. Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras. Cell Chemical Biology 2021, 28:648-661.e5.
- Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs.Alabi S, Crews C. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. The Journal Of Biological Chemistry 2021, 296:100647.
- Targeted protein degradation: A promise for undruggable proteins.Samarasinghe KTG, Crews CM. Targeted protein degradation: A promise for undruggable proteins. Cell Chemical Biology 2021, 28:934-951.
- Synthesis of Isoquinolones by Sequential Suzuki Coupling of 2-Halobenzonitriles with Vinyl Boronate Followed by Cyclization.Jaime-Figueroa S, Bond MJ, Vergara JI, Swartzel JC, Crews CM. Synthesis of Isoquinolones by Sequential Suzuki Coupling of 2-Halobenzonitriles with Vinyl Boronate Followed by Cyclization. The Journal Of Organic Chemistry 2021, 86:8479-8488.
- Electrophilic Screening Platforms for Identifying Novel Covalent Ligands for E3 Ligases.Zheng S, Crews CM. Electrophilic Screening Platforms for Identifying Novel Covalent Ligands for E3 Ligases. Biochemistry 2021, 60:2367-2370.
- Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation.Bond MJ, Crews CM. Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. RSC Chemical Biology 2021, 2:725-742.
- Recent Developments in PROTAC-mediated Protein Degradation: From Bench to Clinic.Crews CM, Hu Z. Recent Developments in PROTAC-mediated Protein Degradation: From Bench to Clinic. Chembiochem : A European Journal Of Chemical Biology 2021.