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Craig M. Crews
BornJune 1, 1964 (1964-06) (age 60)
Alma materUniversity of Virginia
Harvard University
Known forProteolysis Targeting Chimeras (PROTACs)
Controlled Proteostasis
Carfilzomib
AwardsAACR Award for Outstanding Achievement in Chemistry in Cancer Research (2017)
Pierre Fabre Award (2018)
RSC Khorana Prize (2018)
Heinrich Wieland Prize (2020)
Scheele Prize (2021)
Jacob and Louise Gabbay Award (2023)
Scientific career
FieldsChemical Biology
InstitutionsYale University
Doctoral advisorsRaymond L. Erikson
Stuart Schreiber (Postdoctoral Advisor)

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]

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.[6]

Academic career

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In 1995, Crews joined Yale University as an assistant professor in Molecular, Cellular, and Developmental Biology.[12] His research has significantly advanced the field of chemical biology, especially in the area of targeted protein degradation. At Yale, he also serves as the executive director of the Yale Center for Molecular Discovery.[13]

In December 2023, Crews was honored with the 2024 Kimberly Prize in Biochemistry and Molecular Genetics by Northwestern University Feinberg School of Medicine and the Simpson Querrey Institute for Epigenetics.[14]

Crews has contributed to the development of induced proximity as a strategy in drug discovery. This approach involves bringing proteins into close spatial proximity to produce specific biological effects and is central to targeted protein degradation and related therapeutic methods.[15] His work helped demonstrate the potential of this concept, particularly through the development of PROTACs (proteolysis-targeting chimeras), which use the cell’s degradation system to remove certain proteins.[16]

Crews received the Scheele Prize in 2021 and the Passano Award in 2025, the latter shared with Ray Deshaies for their contributions to the development of targeted protein degradation technologies.[17]

Research

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Crews has pioneered the use of ‘induced proximity’ in drug development, specifically, controlled proteostasis, i.e., the pharmacological modulation of protein turnover.[18] In 2001, Crews developed, in collaboration with Ray Deshaies, proteolysis targeting chimeras (PROTACs),[19][20] a new technology to induce proteolysis.[18] 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.[21] This technology has the potential to allow pharmacological targeting of proteins previously thought "undruggable" including many responsible for drug resistance in cancer.[22] Excitement around the field has resulted in much private and public investment in therapeutic approaches based on targeted protein degradation.[23] 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.[24] Subsequent medicinal chemistry efforts produced the epoxyketone containing proteasome inhibitor YU101,[25] which served as the basis for the multiple myeloma drug carfilzomib.[26][27]

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.[28][29] Subsequent medicinal chemistry efforts by Crews produced the epoxyketone-containing proteasome inhibitor, YU101.[30]

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).[31] Based on successful Phase II trials of carfilzomib, Onyx Pharmaceuticals acquired Proteolix in 2009 and was itself acquired by Amgen in 2013.[32][33] Carfilzomib was approved by FDA to treat multiple myeloma in 2012.[34]

In 2024, Crews co-authored a study on the development of ligands and degraders targeting MAGE-A3, a melanoma-associated antigen expressed in various tumors. The research focused on designing small-molecule ligands capable of binding to MAGE-A3 and modulating its interaction with the RING E3 ligase TRIM28.[35] This approach leverages targeted protein degradation technology to influence the ubiquitination and degradation of specific proteins, opening new possibilities for cancer therapy.[36] This work exemplifies the growing potential of targeted protein degradation in the treatment of cancer and other diseases by specifically targeting tumor-associated antigens and their interacting E3 ligases.[37]

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.[38]

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.[22][23] 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.[39]

He and collaborator Ray Deshaies first developed the PROTAC concept in 2001.[40] 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.[41] 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.[22]

Biotechnology companies

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Crews has founded two 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.[42] 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.[43]

As of 2023, Arvinas has four PROTAC therapies in clinical trials.[44] 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.[45] Phase 1/2 data have shown promising safety, tolerability, and pharmacokinetics for both drugs, and both drugs appeared to be well tolerated .[43][46] Moreover, ongoing clinical trials have demonstrated evidence of efficacy in breast tumors with mutated estrogen receptor.[46][47]

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.[48] Unlike PROTACs, RIPTACs do not directly elicit degradation of a target protein.[49] 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.[50] 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 August 2024, Halda Therapeutics, a biotechnology company founded by Crews, secured $126 million in a Series B extension financing. This funding aims to advance Halda's proprietary RIPTAC (Regulated Induced Proximity Targeting Chimeras) platform, which employs a "hold and kill" mechanism to selectively target and eliminate cancer cells. The company initiated a Phase 1 clinical trial for its lead candidate, HLD-0915, in patients with metastatic castration-resistant prostate cancer in January 2025.[51][52][53][54]

Publications

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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". Proceedings of the National Academy of Sciences. 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. ^ "Out of the Lab, Into the World". medicine.yale.edu. Retrieved May 14, 2025.
  13. ^ "PROTAC Research Takes Aim at Drug Resistant Prostate Cancer". medicine.yale.edu. Retrieved May 14, 2025.
  14. ^ Hathaway, Bill (December 13, 2023). "Yale scientist honored for contributions to treatment of cancer | Yale News". news.yale.edu. Retrieved May 14, 2025.
  15. ^ Mullard, Asher (February 28, 2025). "Induced proximity pushes beyond protein degraders, as first RIPTAC moves into the clinic". Nature Reviews Drug Discovery. 24 (4): 235–237. doi:10.1038/d41573-025-00037-7. ISSN 1474-1784.
  16. ^ "Craig Crews on "Induced Proximity: Exploring New Therapeutic Modalities" at ICR - OncoDaily". oncodaily.com. September 10, 2024. Retrieved May 14, 2025.
  17. ^ "Craig M. Crews". Connecticut Academy of Science and Engineering. Retrieved May 14, 2025.
  18. ^ 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.
  19. ^ "PROTACs: A New Type of Drug That Can Target All Disease-Causing Proteins". SciTechDaily. June 11, 2015. Retrieved May 22, 2016.
  20. ^ "Scientist wants to hijack cells' tiny garbage trucks to fight cancer". Boston Globe. May 19, 2016. Retrieved May 22, 2016.
  21. ^ "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.
  22. ^ 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.
  23. ^ 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.
  24. ^ "Carfilzomib: The Latest Triumph of Targeted Therapies Development". Yale Scientific. November 10, 2012. Retrieved May 22, 2016.
  25. ^ "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.
  26. ^ "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.
  27. ^ "Craig Crews, PhD". medicine.yale.edu. Retrieved August 20, 2021.
  28. ^ "Carfilzomib: The Latest Triumph of Targeted Therapies Development – Yale Scientific Magazine". www.yalescientific.org. Retrieved December 11, 2023.
  29. ^ Kim, K. B.; Fonseca, F. N.; Crews, C. M. (2005). "Development and Characterization of Proteasome Inhibitors". Ubiquitin and Protein Degradation, Part B. 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.
  30. ^ "Dr. Crews describes his discovery". healthtree.org. Retrieved December 11, 2023.
  31. ^ Kim, K. B.; Crews, C. M. (2013). "From Epoxomicin to Carfilzomib: Chemistry, Biology, and Medical Outcomes". Natural Product Reports. 30 (5): 600–604. doi:10.1039/c3np20126k. PMC 3815659. PMID 23575525.
  32. ^ "Onyx strikes $851M deal to buy Proteolix".
  33. ^ McCaffrey, Kevin (August 26, 2013). "Kyprolis growth prospects at center of Amgen-Onyx deal". MM+M - Medical Marketing and Media. Retrieved December 11, 2023.
  34. ^ "CENTER FOR DRUG EVALUATION AND RESEARCH (PDF)" (PDF). Archived from the original (PDF) on April 18, 2016.
  35. ^ Li, Ke; Krone, Mackenzie W.; Butrin, Arseniy; Bond, Michael J.; Linhares, Brian M.; Crews, Craig M. (September 11, 2024). "Development of Ligands and Degraders Targeting MAGE-A3". Journal of the American Chemical Society. 146 (36): 24884–24891. doi:10.1021/jacs.4c05393. ISSN 0002-7863.
  36. ^ Philippidis, Alex (August 16, 2024). "Hold and Kill: Halda Raises $126M toward Precision Cancer Treatments". GEN - Genetic Engineering and Biotechnology News. Retrieved May 14, 2025.
  37. ^ mrr5831 (December 5, 2023). "Pioneering Biochemist Craig Crews Named Winner of 2024 Kimberly Prize". News Center. Retrieved May 14, 2025.{{cite web}}: CS1 maint: numeric names: authors list (link)
  38. ^ "Recorded Webinar: From Kyprolis to PROTACs — Insights with Amgen's Ray Deshaies". www.collaborativedrug.com. Retrieved December 11, 2023.
  39. ^ 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.
  40. ^ 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.
  41. ^ "How Chemists Are Sending Bad Proteins Out With The Cellular Trash". Chemical & Engineering News. Retrieved December 11, 2023.
  42. ^ "Protein Degradation with PROTAC Protein Degraders". Arvinas. Retrieved December 11, 2023.
  43. ^ 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.
  44. ^ "Pioneering the future of targeted protein degradation therapeutics (PDF)".
  45. ^ "Arvinas and Pfizer Announce Global Collaboration to Develop and Commercialize PROTAC® Protein Degrader ARV-471 | Pfizer". www.pfizer.com. Retrieved December 11, 2023.
  46. ^ 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".
  47. ^ "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)".
  48. ^ "Craig Martine Crews (PDF)" (PDF).
  49. ^ "Halda emerges from stealth with bifunctional molecules to treat cancer". Chemical & Engineering News. Retrieved December 11, 2023.
  50. ^ 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
  51. ^ Philippidis, Alex (2024). "Hold and Kill: Halda Raises $126M toward Precision Cancer Treatments". GEN Edge. 6 (1): 716–720. doi:10.1089/genedge.6.1.137.
  52. ^ "Yale spinout Halda founded by Craig Crews raises $126M to advance 'hold and kill' solid tumor drugs into the clinic | Yale Ventures". ventures.yale.edu. Retrieved May 14, 2025.
  53. ^ "Halda Therapeutics Raises $126M in Series B Extension to Advance Two Cancer Candidates". BioSpace. August 12, 2024. Retrieved May 14, 2025.
  54. ^ "Siduma Therapeutics". Siduma Therapeutics. Retrieved December 11, 2023.
  55. ^ a b c d e f g "Craig Crews | Department of Chemistry". chem.yale.edu. Retrieved December 11, 2023.
  56. ^ "Profile". www.humboldt-foundation.de. Retrieved December 11, 2023.
  57. ^ "Leadership". Arvinas. Retrieved December 11, 2023.
  58. ^ "Crews awarded UCB-Ehrlich Award for work on anti-cancer therapy". YaleNews. August 18, 2014. Retrieved December 11, 2023.
  59. ^ Agnew, Vicky. "Craig Crews, PhD, receives NCI's Outstanding Investigator Award". medicine.yale.edu. Retrieved December 11, 2023.
  60. ^ "Craig M. Crews, PhD receives the Yale Cancer Center Translational Research Prize". www.yalecancercenter.org. Retrieved December 11, 2023.
  61. ^ "Yale's Craig Crews is recipient of cancer research award". YaleNews. February 28, 2017. Retrieved December 11, 2023.
  62. ^ "Chemistry Biology Interface open prize: Khorana Prize". Royal Society of Chemistry. Retrieved December 11, 2023.
  63. ^ "Craig Crews receives 2018 Pierre Fabre Award for Therapeutic Innovation | Department of Chemistry". chem.yale.edu. Retrieved December 11, 2023.
  64. ^ "2019 Award Winners". www. Retrieved December 11, 2023.
  65. ^ "2020: Professor Dr Craig M. Crews - Heinrich Wieland Prize - Homepage". www.heinrich-wieland-prize.de. Retrieved December 11, 2023.
  66. ^ "Awards & Honors". www.yalecancercenter.org. Retrieved December 11, 2023.
  67. ^ Hathaway, Bill (May 16, 2022). "Yale scientist receives Connecticut Medal of Technology for pioneering work". YaleNews. Retrieved December 11, 2023.
  68. ^ "Scientists Craig Crews and Raymond Deshaies selected for Gabbay Award". BrandeisNOW. Retrieved December 11, 2023.
  69. ^ "Bristol Myers Squibb Award in Enzyme Chemistry – Division of Biological Chemistry". Retrieved December 11, 2023.
  70. ^ [email protected] (January 31, 2024). "The 2024 IUPAC-Richter Award Goes to Craig M. Crews". IUPAC | International Union of Pure and Applied Chemistry. Retrieved May 14, 2025.
  71. ^ Baltimore, University of Maryland. "Calendar - The Elm". calendar.umaryland.edu. Retrieved May 14, 2025.
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