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Craig M. Crews

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Craig M. Crews (born June 1, 1964) is an American scientist at Yale University known for his contributions to chemical biology. He is known for his contributions to the field of induced proximity through his work in creating heterobifunctional molecules that "hijack" cellular processes by inducing the interaction of two proteins inside a living cell.[1] His initial work focused on the discovery of PROteolysis-TArgeting Chimeras (PROTACs) to trigger degradation of disease-causing proteins, a process known as targeted protein degradation (TPD), and he has since developed new versions of -TACs to leverage other cellular processes and protein families to treat disease.[2]

Craig M. Crews
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)

At Yale University, he holds the John C. Malone Professorship in Molecular, Cellular, and Developmental Biology, and also holds joint appointments in the departments of Chemistry and Pharmacology.[3][4] Crews founded, and is the Executive Director of, the Yale Center for Molecular Discovery.[5]

Education and training

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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.[6] As a graduate student in the laboratory of Raymond Erikson at Harvard University, Crews was the first to purify and clone the MAP kinase kinase MEK1,[7][8] a key signaling molecule controlling cancer-driving cellular processes including proliferation and survival.[9][10] Targeting MEK1 for the treatment of cancer has since been pursued by several biotechnology companies.[11]

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.[6]

Research

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Crews studies controlled proteostasis, i.e., the pharmacological modulation of protein turnover.[12] In 2001, Crews developed, in collaboration with Ray Deshaies, proteolysis targeting chimeras (PROTACs),[13][14] a new technology to induce proteolysis.[12] 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.[15] This technology has the potential to allow pharmacological targeting of proteins previously thought "undruggable" including many responsible for drug resistance in cancer.[16] Excitement around the field has resulted in much private and public investment in therapeutic approaches based on targeted protein degradation.[17] 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.[18] Subsequent medicinal chemistry efforts produced the epoxyketone containing proteasome inhibitor YU101,[19] which served as the basis for the multiple myeloma drug carfilzomib.[20][21]

Crews’ initial research at Yale explored the synthesis and mode of action of the natural product epoxomicin, which revealed itself to be a potent and selective proteasome inhibitor via its epoxyketone pharmacophore.[22][23] Subsequent medicinal chemistry efforts by Crews produced the epoxyketone-containing proteasome inhibitor, YU101.[24]

In 2003, Crews co-founded the biotechnology company Proteolix to develop YU101, which ultimately served as the parent compound of multiple myeloma drug carfilzomib (Kyprolis).[25] Based on successful Phase II trials of carfilzomib, Onyx Pharmaceuticals acquired Proteolix in 2009 and was itself acquired by Amgen in 2013.[26][27] Carfilzomib was approved by FDA to treat multiple myeloma in 2012.[28]

Induced Proximity

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Crews’ work on proteasome inhibitors ultimately inspired the concept of induced proximity, beginning with using heterobifunctional molecules, now known as PROTACs, to hijack the cell’s degradation machinery to induce degradation of target proteins.[29]

Crews’ work in the field of induced proximity has led to the development of a number of investigational therapeutic candidates aimed at drugging proteins that are difficult to target using existing small molecule technology.[16][17] A clinically advanced PROTAC, ARV-471, is being developed by Crews’ company Arvinas and is the first induced heterobifunctional proximity molecule to demonstrate clinical proof-of-concept.[30]

He and collaborator Ray Deshaies first developed the PROTAC concept in 2001.[31] PROTACs are heterobifunctional molecules that initiate proteasome-dependent removal of specific proteins by simultaneously binding the protein and a ubiquitin ligase (i.e., an E3 ubiquitin ligase). The induced proximity of target and ligase catalyzes ubiquitination of the target protein, tagging the target protein for recognition by the proteasome.[32] PROTACs have the potential to allow pharmacological targeting of proteins previously thought "undruggable", such as those with inaccessible or non-selective active sites, including many responsible for drug resistance in cancer.[16]

Biotechnology companies

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Crews has founded three biotechnology companies to develop TACs discovered in his Yale research lab, each of which induces protein-protein interactions within distinct target classes to achieve a therapeutic effect.

In 2013, Crews founded New Haven-based Arvinas, which uses the PROTAC technology discovered in his lab to develop drugs to treat cancer, neurodegeneration, and other diseases.[33] Notably, Arvinas’ PROTAC drugs have successfully demonstrated oral availability in clinical trials, overcoming a key challenge faced by PROTACs-based drug development since conception, owing to their atypically large size and pharmacological properties.[34]

As of 2023, Arvinas has three PROTAC therapies in clinical trials.[35] The most advanced is vepdegestrant (ARV-471), a PROTAC targeting the Estrogen Receptor, in Phase 3 trials to treat metastatic breast cancer. In 2021, Arvinas and Pfizer, Inc. partnered to co-develop vepdegestrant.[36] Phase 1/2 data have shown promising safety, tolerability, and pharmacokinetics for both drugs, and both drugs appeared to be well tolerated .[34][37] Moreover, ongoing clinical trials have demonstrated evidence of efficacy.[37][38]

In 2019, Crews founded Halda Therapeutics, a venture-backed biotech company that is developing RIPTACs, or Regulated Induced Proximity Targeting Chimeras, for the treatment of cancer.[39] Unlike PROTACs, RIPTACs do not directly elicit degradation of a target protein.[40] Instead, RIPTACs induce the formation of a stable complex between a target protein selectively expressed in cancer tissue and a more widely expressed protein essential for cell survival.[41] The resulting cooperative protein:protein interaction (PPI) abrogates the function of the essential protein, thus leading to the death of cancer cells expressing the target protein.

In 2021, Crews founded Siduma Therapeutics to advance other novel heterobifunctional concepts with broad utility in drug development.[42]

Publications

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  • Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ (July 2001). "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. 98 (15): 8554–9. Bibcode:2001PNAS...98.8554S. doi:10.1073/pnas.141230798. PMC 37474. PMID 11438690.
  • Crews, C. M.; Alessandrini, A.; Erikson, R. L. (October 16, 1992). "The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product". Science. 258 (5081): 478–480. Bibcode:1992Sci...258..478C. doi:10.1126/science.1411546. ISSN 0036-8075. PMID 1411546.
  • Meng, L.; Mohan, R.; Kwok, B. H.; Elofsson, M.; Sin, N.; Crews, C. M. (August 31, 1999). "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. 96 (18): 10403–10408. doi:10.1073/pnas.96.18.10403. ISSN 0027-8424. PMC 17900. PMID 10468620.
  • Lai, Ashton C.; Crews, Craig M. (2017). "Induced protein degradation: an emerging drug discovery paradigm". Nature Reviews. Drug Discovery. 16 (2): 101–114. doi:10.1038/nrd.2016.211. ISSN 1474-1784. PMC 5684876. PMID 27885283.
  • 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; Grandi, Paola; Shimamura, Satoko; Bergamini, Giovanna; Faelth-Savitski, Maria (2015). "Catalytic in vivo protein knockdown by small-molecule PROTACs". Nature Chemical Biology. 11 (8): 611–617. doi:10.1038/nchembio.1858. ISSN 1552-4469. PMC 4629852. PMID 26075522.

Awards and recognition

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References

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  1. ^ "Hijacking protein degradation". Nature Chemical Biology. 16 (11): 1151. 2020. doi:10.1038/s41589-020-00685-3. ISSN 1552-4469. PMID 33067603.
  2. ^ Bond, Michael J.; Crews, Craig M. (June 10, 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. ISSN 2633-0679. PMC 8190915. PMID 34212149.
  3. ^ a b "Crews Laboratory". crewslab.yale.edu. Retrieved December 11, 2023.
  4. ^ "Craig Crews named the John C. Malone Professor". medicine.yale.edu. Retrieved December 11, 2023.
  5. ^ "Yale Small Molecule Discovery Center". Yale Medicine. April 29, 2012. Retrieved December 11, 2023.
  6. ^ a b c "Crews Laboratory". crewslab.yale.edu. Retrieved August 20, 2021.
  7. ^ Crews CM, Alessandrini A, Erikson RL (October 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.
  8. ^ Crews CM, Erikson RL (September 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.
  9. ^ Crews, Craig M.; Alessandrini, Alessandro; Erikson, Raymond L. (October 1, 1992). "The Primary Structure of MEK, a Protein Kinase That Phosphorylates the ERK Gene Product". Science. 258 (5081): 478–480. Bibcode:1992Sci...258..478C. doi:10.1126/science.1411546. ISSN 0036-8075. PMID 1411546.
  10. ^ Crews, C. M.; Erikson, R. L. (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". National Library of Medicine. 89 (17): 8205–8209. Bibcode:1992PNAS...89.8205C. doi:10.1073/pnas.89.17.8205. PMC 49886. PMID 1381507.
  11. ^ Caunt, Christopher J.; Sale, Matthew J.; Smith, Paul D.; Cook, Simon J. (2015). "MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road". Nature Reviews. Cancer. 15 (10): 577–592. doi:10.1038/nrc4000. ISSN 1474-1768. PMID 26399658.
  12. ^ a b Bond MJ, Crews CM (March 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. PMC 8190915. PMID 34212149.
  13. ^ "PROTACs: A New Type of Drug That Can Target All Disease-Causing Proteins". SciTechDaily. June 11, 2015. Retrieved May 22, 2016.
  14. ^ "Scientist wants to hijack cells' tiny garbage trucks to fight cancer". Boston Globe. May 19, 2016. Retrieved May 22, 2016.
  15. ^ "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. January 18, 2016. Retrieved May 5, 2016.
  16. ^ a b c Sun X, Gao H, Yang Y, He M, Wu Y, Song Y, et al. (December 24, 2019). "PROTACs: great opportunities for academia and industry". Signal Transduction and Targeted Therapy. 4 (1): 64. doi:10.1038/s41392-019-0101-6. PMC 6927964. PMID 31885879.
  17. ^ a b Roots Analysis. "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". Cision (Press release). Retrieved May 12, 2020.
  18. ^ "Carfilzomib: The Latest Triumph of Targeted Therapies Development". Yale Scientific. November 10, 2012. Retrieved May 22, 2016.
  19. ^ "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". September 12, 2013. Retrieved April 24, 2018.
  20. ^ "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". The Myeloma Crowd. Retrieved August 20, 2021.
  21. ^ "Craig Crews, PhD". medicine.yale.edu. Retrieved August 20, 2021.
  22. ^ "Carfilzomib: The Latest Triumph of Targeted Therapies Development – Yale Scientific Magazine". www.yalescientific.org. Retrieved December 11, 2023.
  23. ^ Kim, K. B.; Fonseca, F. N.; Crews, C. M. (2005). Development and Characterization of Proteasome Inhibitors. Methods in Enzymology. Vol. 399. pp. 585–609. doi:10.1016/S0076-6879(05)99039-3. ISBN 978-0-12-182804-2. PMC 2556561. PMID 16338383. {{cite book}}: |journal= ignored (help)
  24. ^ "Dr. Crews describes his discovery". healthtree.org. Retrieved December 11, 2023.
  25. ^ Kim, K. B.; Crews, C. M. (2013). "From Epoxomicin to Carfilzomib: Chemistry, Biology, and Medical Outcomes". National Library of Medicine. 30 (5): 600–604. doi:10.1039/c3np20126k. PMC 3815659. PMID 23575525.
  26. ^ "Onyx strikes $851M deal to buy Proteolix".
  27. ^ McCaffrey, Kevin (August 26, 2013). "Kyprolis growth prospects at center of Amgen-Onyx deal". MM+M - Medical Marketing and Media. Retrieved December 11, 2023.
  28. ^ "CENTER FOR DRUG EVALUATION AND RESEARCH (PDF)" (PDF).
  29. ^ "Recorded Webinar: From Kyprolis to PROTACs — Insights with Amgen's Ray Deshaies". www.collaborativedrug.com. Retrieved December 11, 2023.
  30. ^ Liu, Z.; Hu, M.; Yang, Y.; Du, C.; Zhou, H.; Liu, C.; Chen, Y.; Fan, L.; Ma, H.; Gong, Y.; Xie, Y. (2022). "An overview of PROTACs: a promising drug discovery paradigm". Molecular Biomedicine. 3 (1): 46. doi:10.1186/s43556-022-00112-0. PMC 9763089. PMID 36536188.
  31. ^ Sakamoto, Kathleen M.; Kim, Kyung B.; Kumagai, Akiko; Mercurio, Frank; Crews, Craig M.; Deshaies, Raymond J. (July 17, 2001). "Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation". Proceedings of the National Academy of Sciences. 98 (15): 8554–8559. Bibcode:2001PNAS...98.8554S. doi:10.1073/pnas.141230798. ISSN 0027-8424. PMC 37474. PMID 11438690.
  32. ^ "How Chemists Are Sending Bad Proteins Out With The Cellular Trash". Chemical & Engineering News. Retrieved December 11, 2023.
  33. ^ "Protein Degradation with PROTAC Protein Degraders". Arvinas. Retrieved December 11, 2023.
  34. ^ a b Mullard, Asher (November 6, 2019). "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.
  35. ^ "Pioneering the future of targeted protein degradation therapeutics (PDF)".
  36. ^ "Arvinas and Pfizer Announce Global Collaboration to Develop and Commercialize PROTAC® Protein Degrader ARV-471 | Pfizer". www.pfizer.com. Retrieved December 11, 2023.
  37. ^ a b "Potential of Arvinas' PROTAC® AR Degraders Reinforced by 11.1 months rPFS with Bavdegalutamide and Updated Positive Interim Data from Second Generation ARV-766 in mCRPC".
  38. ^ "Arvinas Announces ARV-471 Achieves a Clinical Benefit Rate of 38% in Evaluable Patients and Continues to Show a Favorable Tolerability Profile in its Phase 2 Expansion Trial (VERITAC)".
  39. ^ "Craig Martine Crews (PDF)" (PDF).
  40. ^ "Halda emerges from stealth with bifunctional molecules to treat cancer". Chemical & Engineering News. Retrieved December 11, 2023.
  41. ^ Raina, Kanak; Forbes, Chris D.; Stronk, Rebecca; Rappi, Jonathan P.; Eastman, Kyle J.; Gerritz, Samuel W.; Yu, Xinheng; Li, Hao; Bhardwaj, Amit (January 2, 2023), "Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic Strategy for Killing Cancer Cells Selectively", bioRxiv: The Preprint Server for Biology: 2023.01.01.522436, doi:10.1101/2023.01.01.522436, PMC 9881854, PMID 36711980, retrieved December 11, 2023
  42. ^ "Siduma Therapeutics". Siduma Therapeutics. Retrieved December 11, 2023.
  43. ^ a b c d e f g "Craig Crews | Department of Chemistry". chem.yale.edu. Retrieved December 11, 2023.
  44. ^ "Profile". www.humboldt-foundation.de. Retrieved December 11, 2023.
  45. ^ "Leadership". Arvinas. Retrieved December 11, 2023.
  46. ^ "Crews awarded UCB-Ehrlich Award for work on anti-cancer therapy". YaleNews. August 18, 2014. Retrieved December 11, 2023.
  47. ^ Agnew, Vicky. "Craig Crews, PhD, receives NCI's Outstanding Investigator Award". medicine.yale.edu. Retrieved December 11, 2023.
  48. ^ "Craig M. Crews, PhD receives the Yale Cancer Center Translational Research Prize". www.yalecancercenter.org. Retrieved December 11, 2023.
  49. ^ "Yale's Craig Crews is recipient of cancer research award". YaleNews. February 28, 2017. Retrieved December 11, 2023.
  50. ^ "Chemistry Biology Interface open prize: Khorana Prize". Royal Society of Chemistry. Retrieved December 11, 2023.
  51. ^ "Craig Crews receives 2018 Pierre Fabre Award for Therapeutic Innovation | Department of Chemistry". chem.yale.edu. Retrieved December 11, 2023.
  52. ^ "2019 Award Winners". www. Retrieved December 11, 2023.
  53. ^ "2020: Professor Dr Craig M. Crews - Heinrich Wieland Prize - Homepage". www.heinrich-wieland-prize.de. Retrieved December 11, 2023.
  54. ^ "Awards & Honors". www.yalecancercenter.org. Retrieved December 11, 2023.
  55. ^ Hathaway, Bill (May 16, 2022). "Yale scientist receives Connecticut Medal of Technology for pioneering work". YaleNews. Retrieved December 11, 2023.
  56. ^ "Scientists Craig Crews and Raymond Deshaies selected for Gabbay Award". BrandeisNOW. Retrieved December 11, 2023.
  57. ^ "Bristol Myers Squibb Award in Enzyme Chemistry – Division of Biological Chemistry". Retrieved December 11, 2023.
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