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Craig M. Crews

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Craig M. Crews
File:Craig Crews.jpg
BornJune 1, 1964 (1964-06) (age 60)
Alma materUniversity of Virginia
Harvard University
Known forProteolysis Targeting Chimeras (PROTACs)
Controlled Proteostasis
Carfilzomib
AwardsFriedrich Wilhelm Bessel Research Award (Alexander von Humboldt Foundation) (2005)
UCB-Ehrlich Award for Excellence in Medicinal Chemistry (2014)
National Cancer Institute Outstanding Investigator Award (2015)
AACR Award for Outstanding Achievement in Chemistry in Cancer Research (2017)
Pierre Fabre Award (2018)
RSC Khorana Prize (2018)
Scientific career
FieldsChemical Biology
InstitutionsYale University
Doctoral advisorsRaymond L. Erikson
Stuart Schreiber (Postdoctoral Advisor)

Craig M. Crews, Ph.D. (born June 1, 1964) is an American scientist at Yale University. He is the John C. Malone Professor of Molecular, Cellular, and Developmental Biology, and also holds joint appointments in the departments of Chemistry and Pharmacology. Crews is the Executive Director of the Yale Center for Molecular Discovery and a former Editor of Cell Chemical Biology.[1][2] His research interests focus on Chemical Biology, particularly on controlled proteostasis. Crews is a pioneer in the field of Targeted Protein Degradation and his lab's research led to the development of the FDA approved anti-cancer drug Carfilzomib (Kyprolis®).[3]

Education and training

Crews graduated from the University of Virginia in 1986 with a bachelor's degree in Chemistry, after which he performed research at the University of Tübingen as a German Academic Exchange Service (DAAD) Fellow.[4] As a graduate student in the laboratory of Raymond Erikson at Harvard University, Crews purified and cloned the MAP kinase kinase MEK1,[5][6] a key kinase that controls cell growth. He subsequently worked in the research group of Stuart Schreiber as a Cancer Research Institute Fellow before joining the faculty of Yale University as an assistant professor in Molecular, Cellular, and Developmental Biology in 1995.[4]

Research

Crews studies controlled proteostasis, i.e., the pharmacological modulation of protein turnover.[7] In 2001, Crews developed (in collaboration with Ray Deshaies) PROTACs (Proteolysis Targeting Chimeras),[8][9] a new technology to induce proteolysis.[7] PROTACs are dimeric molecules that recruit specific intracellular proteins to the cellular quality control machinery (i.e., an E3 ubiquitin ligase) in a catalytic manner for subsequent removal by the proteasome.[10] This technology has the potential to allow pharmacological targeting of proteins previously thought "undruggable" including many responsible for drug resistance in cancer.[11] Excitement around the field has resulted in much private and public investment in therapeutic approaches based on targeted protein degradation.[12] Prior to its work on PROTACs, the Crews lab’s synthesis and mode of action studies of the natural product epoxomicin revealed that it is a potent and selective proteasome inhibitor.[13] Subsequent medicinal chemistry efforts produced the epoxyketone containing proteasome inhibitor YU101,[14] which served as the basis for the multiple myeloma drug Carfilzomib (Kyprolis®).[15][16]

Arvinas

In 2013, Crews founded New Haven-based Arvinas, which uses the PROTAC protein degradation technology from his lab to develop drugs to treat cancer, neurodegeneration, and other diseases. In 2019, Arvinas presented initial safety, tolerability, and pharmacokinetic data from the company’s ongoing Phase 1 clinical trials of two orally bioavailable PROTACs, targeting the Androgen Receptor (ARV-110) and the Estrogen Receptor (ARV-471).[17] Both drugs appeared to be well tolerated and no dose-limiting toxicities or grade 2, 3 or 4 adverse events were observed.[18] Moreover, ongoing clinical trials have demonstrated evidence of efficacy, e.g., target protein level reduction and tumor shrinkage in some patients.[19][20]

Proteolix

In 2003, Crews co-founded the biotechnology company Proteolix to develop YU101, the next generation proteasome inhibitor from his lab, which ultimately became carfilzomib. Marketed under the trade name Kyprolis®, carfilzomib was approved by the FDA on June 20, 2012 for use in patients with multiple myeloma.[21] Based on successful Phase II trials of carfilzomib, Onyx Pharmaceuticals acquired Proteolix in 2009 [22] and was itself acquired by Amgen in 2013.[23]

Awards and recognition

Publications

  • Bond M, Chu L, Nalawansha D, Li K, Crews CM. Targeted Degradation of Oncogenic KRASG12C by VHL-recruiting PROTACs. ACS Central Science, 6(8):1367–1375.[32]
  • Cromm PM, Samarasinghe KTG, Hines J, Crews CM Addressing Kinase-independent Functions of FAK via PROTAC-mediated Degradation. J American Chemical Society 140(49): 17026-17026.[33]
  • Burslem GM, Smith BE, Lai A, Jaime-Figueroa S, McQuaid D, Bondeson DP, Toure M, Dong H, Qian Y, Wang J, Crew AP, Hines J, Crews CM. The advantages of targeted protein degradation over inhibition: a RTK case study. Cell Chemical Biology 25:67-77.[34]
  • Salami J and Crews CM. Waste Disposal- An attractive strategy for cancer therapy Science 355(6330):1163-1167.[35]
  • 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. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nature Chemical Biology 2015 11(8):611-7.[36]
  • Lai, AC, Toure, M, Hellerschmied, D, Salami, J, Jaime-Figueroa, S, Ko, E, Hines, J, Crews, CM. Accessing oncogenic BCR-ABL for degradation by modular PROTAC design. Angewandte Chemie Int. Ed. Engl. 55:807–810.[37]
  • Gustafson JL, Neklesa TK, Cox CS, Roth AG, Buckley DL, Tae H-S, Sundberg TB, Crews CM. Making the problem go away: Targeted androgen receptor degradation overcomes resistance to prostate cancer therapy. Angewandte Chemie Int. Ed. Engl. 2015 Aug 10;54(33):9659-62.[38]
  • Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Himes J, Winkler JD, Crew AP, Coleman K, Crews CM. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chemistry & Biology 22:1-9.[39]
  • Buckley DL, Van Molle I, Gareiss PC, Tae H-S, Michel J, Noblin DJ, Jorgensen WL, Ciulli A, and CM Crews. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1alpha interaction. J American Chemical Society 134(10):4465-8.[40]
  • Schneekloth Jr., JS, F Fonseca, M Koldobskiy, A Mandal, R Deshaies, K Sakamoto, and CM Crews. Chemical genetic control of protein levels: Selective in vivo targeted degradation J American Chemical Society 126(12):3748-54.[41]
  • Sakamoto KM, KB Kim, A Kumagai, F Mercurio, CM Crews, and RJ Deshaies. PROTACs: Chimeric Molecules that Target Proteins to the Skp1-Cullin-F Box Complex for Ubiquitination and Degradation, Proc. Natl. Acad. Sci. USA 98:8554-8559.[42]
  • Crews CM, AA Alessandrini, and RL Erikson. The primary structure of MEK, a protein kinase that phosphorylates and activates the ERK gene product. Science, 258:478-480.[43]

References

  1. ^ "Staff and Editorial Board". Cell Chemical Biology. Retrieved February 28, 2018.
  2. ^ "Yale Center for Molecular Discovery". Ycmd.yale.edu. Retrieved 2016-05-05.
  3. ^ "Carfilzomib: From Discovery To Drug | August 27, 2012 Issue - Vol. 90 Issue 35 | Chemical & Engineering News". Cen.acs.org. 2012-08-27. Retrieved 2016-05-05.
  4. ^ a b c "Crews Laboratory". crewslab.yale.edu. Retrieved 2021-08-20.
  5. ^ Crews CM, Alessandrini A, Erikson RL (1992). "The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product". Science. 258 (5081): 478–80. Bibcode:1992Sci...258..478C. doi:10.1126/science.1411546. PMID 1411546.
  6. ^ Crews CM, Erikson RL (1992). "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. 89 (17): 8205–9. Bibcode:1992PNAS...89.8205C. doi:10.1073/pnas.89.17.8205. PMC 49886. PMID 1381507.
  7. ^ a b Bond, Michael J.; Crews M., Craig (2021). "Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation". RSC Chemical Biology. 2 (3): 725–742. doi:10.1039/D1CB00011J.
  8. ^ "PROTACs: A New Type of Drug That Can Target All Disease-Causing Proteins". SciTechDaily. 2015-06-11. Retrieved 2016-05-22.
  9. ^ "Scientist wants to hijack cells' tiny garbage trucks to fight cancer". Boston Globe. 2016-05-19. Retrieved 2016-05-22.
  10. ^ "How Chemists Are Sending Bad Proteins Out With The Cellular Trash | January 18, 2016 Issue - Vol. 94 Issue 3 | Chemical & Engineering News". Cen.acs.org. 2016-01-18. Retrieved 2016-05-05.
  11. ^ Sun, Xiuyun; Gao, Hongying; Yang, Yiqing; He, Ming; Wu, Yue; Song, Yugang; Tong, Yan; Rao, Yu (2019-12-24). "PROTACs: great opportunities for academia and industry". Signal Transduction and Targeted Therapy. 4 (1): 64. doi:10.1038/s41392-019-0101-6. ISSN 2059-3635. PMC 6927964. PMID 31885879.
  12. ^ Analysis, Roots. "With Over USD 3.5 Billion in Capital Investment, and Numerous High Value Licensing Deals, the Targeted Protein Degradation Market is Anticipated to Grow at an Annualized Rate of Over 30%, Claims Roots Analysis". www.prnewswire.com. Retrieved 2020-05-12.
  13. ^ "Carfilzomib: The Latest Triumph of Targeted Therapies Development". Yale Scientific. 2012-11-10. Retrieved 2016-05-22.
  14. ^ "Dr. Craig Crews of the Crews Laboratory at Yale University describes his discovery and development of carfilzomib (Kyprolis) and what it takes to get a new drug across the "Valley of Death" - The Myeloma Crowd". 12 September 2013. Retrieved 24 April 2018.
  15. ^ Crowd, The Myeloma. "Dr. Craig Crews of the Crews Laboratory at Yale University describes his discovery and development of carfilzomib (Kyprolis) and what it takes to get a new drug across the finish line in myeloma". www.myelomacrowd.org. Retrieved 2021-08-20.
  16. ^ "Craig Crews, PhD". medicine.yale.edu. Retrieved 2021-08-20.
  17. ^ "Arvinas Presents a Platform Update, Including Initial Data from the First Two Clinical Trials of PROTAC® Targeted Protein Degraders". Arvinas. Retrieved 2020-05-12.
  18. ^ Mullard, Asher (2019-11-06). "Arvinas's PROTACs pass first safety and PK analysis". Nature Reviews Drug Discovery. 18 (12): 895. doi:10.1038/d41573-019-00188-4. PMID 31780851. S2CID 208357723.
  19. ^ "Pfizer Strengthens Cancer Standing with Protein Degrader Collaboration". BioSpace. Retrieved 2021-08-20.
  20. ^ Houlton2021-07-30T14:27:00+01:00, Sarah. "Pfizer backs protein degrader drugs with Arvinas deal". Chemistry World. Retrieved 2021-08-20.{{cite web}}: CS1 maint: numeric names: authors list (link)
  21. ^ "FDA approves Kyprolis for some patients with multiple myeloma". Fda.gov. 2012-07-20. Retrieved 2016-05-05.
  22. ^ "Onyx strikes $851M deal to buy Proteolix". FierceBiotech. Retrieved 2016-05-05.
  23. ^ Kevin McCaffrey. "Kyprolis growth prospects at center of Amgen-Onyx deal - Medical Marketing and Media". Mmm-online.com. Retrieved 2016-05-05.
  24. ^ "Awards & Honors". www.yalecancercenter.org. Retrieved 2021-08-20.
  25. ^ "2020: Professor Dr Craig M. Crews - Heinrich Wieland Prize - Homepage". www.heinrich-wieland-prize.de. Retrieved 2021-08-20.
  26. ^ "2019 Award Winners". Default. Retrieved 2021-08-20.
  27. ^ https://www.rict2018.org/speakers[permanent dead link]
  28. ^ "RSC Khorana Prize 2018 Winner". 2018-05-08. Retrieved 2018-06-01.
  29. ^ "Yale's Craig Crews is recipient of cancer research award". 2017-02-28. Retrieved 2017-03-05.
  30. ^ "Craig Crews, PhD, receives NCI's Outstanding Investigator Award". 2015-10-16. Retrieved 2016-05-22.
  31. ^ "YaleNews | Crews awarded UCB-Ehrlich Award for work on anti-cancer therapy". News.yale.edu. 2014-08-18. Retrieved 2016-05-05.
  32. ^ Bond, Michael J.; Chu, Ling; Nalawansha, Dhanusha A.; Li, Ke; Crews, Craig M. (2020-08-26). "Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs". ACS Central Science. 6 (8): 1367–1375. doi:10.1021/acscentsci.0c00411. ISSN 2374-7943. PMC 7453568. PMID 32875077.{{cite journal}}: CS1 maint: PMC format (link)
  33. ^ Cromm, Philipp M.; Samarasinghe, Kusal T. G.; Hines, John; Crews, Craig M. (2018-12-12). "Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation". Journal of the American Chemical Society. 140 (49): 17019–17026. doi:10.1021/jacs.8b08008. ISSN 0002-7863.
  34. ^ Burslem, George M.; Smith, Blake E.; Lai, Ashton C.; Jaime-Figueroa, Saul; McQuaid, Daniel C.; Bondeson, Daniel P.; Toure, Momar; Dong, Hanqing; Qian, Yimin; Wang, Jing; Crew, Andrew P. (2018-01-18). "The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study". Cell Chemical Biology. 25 (1): 67–77.e3. doi:10.1016/j.chembiol.2017.09.009. ISSN 2451-9448. PMC 5831399. PMID 29129716.
  35. ^ Salami, Jemilat; Crews, Craig M. (2017-03-17). "Waste disposal-An attractive strategy for cancer therapy". Science (New York, N.Y.). 355 (6330): 1163–1167. doi:10.1126/science.aam7340. ISSN 1095-9203. PMID 28302825.
  36. ^ Bondeson, Daniel P; Mares, Alina; Smith, Ian E D; Ko, Eunhwa; Campos, Sebastien; Miah, Afjal H; Mulholland, Katie E; Routly, Natasha; Buckley, Dennis L; Gustafson, Jeffrey L; Zinn, Nico. "Catalytic in vivo protein knockdown by small-molecule PROTACs". Nature chemical biology. 11 (8): 611–617. doi:10.1038/nchembio.1858. ISSN 1552-4450. PMC 4629852. PMID 26075522.
  37. ^ Lai, Ashton C.; Toure, Momar; Hellerschmied, Doris; Salami, Jemilat; Jaime-Figueroa, Saul; Ko, Eunhwa; Hines, John; Crews, Craig M. (2016-01-11). "Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL". Angewandte Chemie (International Ed. in English). 55 (2): 807–810. doi:10.1002/anie.201507634. ISSN 1521-3773. PMC 4733637. PMID 26593377.
  38. ^ Gustafson, Jeffrey L.; Neklesa, Taavi K.; Cox, Carly S.; Roth, Anke G.; Buckley, Dennis L.; Tae, Hyun Seop; Sundberg, Thomas B.; Stagg, D. Blake; Hines, John; McDonnell, Donald P.; Norris, John D. (2015-08-10). "Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging". Angewandte Chemie (International Ed. in English). 54 (33): 9659–9662. doi:10.1002/anie.201503720. ISSN 1521-3773. PMC 4547777. PMID 26083457.
  39. ^ Lu, Jing; Qian, Yimin; Altieri, Martha; Dong, Hanqing; Wang, Jing; Raina, Kanak; Hines, John; Winkler, James; Crew, Andrew; Coleman, Kevin; Crews, Craig (2015-06-18). "Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4". Chemistry and Biology. 22 (6): 755–763. doi:10.1016/j.chembiol.2015.05.009. ISSN 1879-1301. PMC 4475452. PMID 26051217.
  40. ^ Buckley, Dennis L.; Van Molle, Inge; Gareiss, Peter C.; Tae, Hyun Seop; Michel, Julien; Noblin, Devin J.; Jorgensen, William L.; Ciulli, Alessio; Crews, Craig M. (2012-03-14). "Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction". Journal of the American Chemical Society. 134 (10): 4465–4468. doi:10.1021/ja209924v. ISSN 0002-7863. PMC 3448299. PMID 22369643.{{cite journal}}: CS1 maint: PMC format (link)
  41. ^ Schneekloth, John S.; Fonseca, Fabiana N.; Koldobskiy, Michael; Mandal, Amit; Deshaies, Raymond; Sakamoto, Kathleen; Crews, Craig M. "Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation". Journal of the American Chemical Society. 126 (12): 3748–3754. doi:10.1021/ja039025z. ISSN 0002-7863.
  42. ^ "(PDF) Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation". ResearchGate. Retrieved 2021-08-20.
  43. ^ "Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation". www.researchgate.net. Retrieved 1 August 2001.
  1. Crews lab
  2. Yale Center for Molecular Discovery
  3. Arvinas, LLC.
  4. Proteolix, Inc.
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