Craig M. Crews Explained

Craig M. Crews
Field:Chemical Biology
Work Institution:Yale University
Alma Mater:University of Virginia
Harvard University
Doctoral Advisors:Raymond L. Erikson
Stuart Schreiber (Postdoctoral Advisor)
Known For:Proteolysis Targeting Chimeras (PROTACs)
Controlled Proteostasis
Carfilzomib
Prizes:Friedrich 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)

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

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.

Research

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. 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

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. 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.

Biotechnology companies

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.[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. 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.[41]

Publications

Awards and recognition

External links

Notes and References

  1. Hijacking protein degradation . Nature Chemical Biology . 2020 . en . 16 . 11 . 1151 . 10.1038/s41589-020-00685-3 . 1552-4469. free . 33067603 .
  2. Bond . Michael J. . Crews . Craig M. . 2021-06-10 . Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation . RSC Chemical Biology . en . 2 . 3 . 725–742 . 10.1039/D1CB00011J . 2633-0679. free . 34212149 . 8190915 .
  3. Web site: Crews Laboratory . 2023-12-11 . crewslab.yale.edu . en.
  4. Web site: Craig Crews named the John C. Malone Professor . 2023-12-11 . medicine.yale.edu . en.
  5. Web site: 2012-04-29 . Yale Small Molecule Discovery Center . 2023-12-11 . Yale Medicine . en.
  6. Web site: Crews Laboratory. August 20, 2021. crewslab.yale.edu. en.
  7. Crews CM, Alessandrini A, Erikson RL . The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product . Science . 258 . 5081 . 478–80 . October 1992 . 1411546 . 10.1126/science.1411546 . 1992Sci...258..478C .
  8. 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 . 89 . 17 . 8205–9 . September 1992 . 1381507 . 49886 . 10.1073/pnas.89.17.8205 . 1992PNAS...89.8205C . free .
  9. Crews . Craig M. . Alessandrini . Alessandro . Erikson . Raymond L. . 1992-10-01 . The Primary Structure of MEK, a Protein Kinase That Phosphorylates the ERK Gene Product . Science . 258 . 5081 . 478–480 . 10.1126/science.1411546 . 1411546 . 1992Sci...258..478C . 0036-8075.
  10. 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. 1992 . 49886 . Crews . C. M. . Erikson . R. L. . 89 . 17 . 8205–8209 . 10.1073/pnas.89.17.8205 . free . 1381507 . 1992PNAS...89.8205C .
  11. Caunt . Christopher J. . Sale . Matthew J. . Smith . Paul D. . Cook . Simon J. . MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road . Nature Reviews. Cancer . 2015 . 15 . 10 . 577–592 . 10.1038/nrc4000 . 1474-1768 . 26399658.
  12. Bond MJ, Crews CM . Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation . RSC Chemical Biology . 2 . 3 . 725–742 . March 2021 . 34212149 . 10.1039/D1CB00011J . 8190915 .
  13. Web site: PROTACs: A New Type of Drug That Can Target All Disease-Causing Proteins. June 11, 2015. SciTechDaily. May 22, 2016.
  14. Web site: Scientist wants to hijack cells' tiny garbage trucks to fight cancer. May 19, 2016. Boston Globe. May 22, 2016.
  15. Web site: How Chemists Are Sending Bad Proteins Out With The Cellular Trash | January 18, 2016 Issue – Vol. 94 Issue 3 | Chemical & Engineering News. January 18, 2016. Cen.acs.org. May 5, 2016.
  16. Sun X, Gao H, Yang Y, He M, Wu Y, Song Y, Tong Y, Rao Y . 6 . PROTACs: great opportunities for academia and industry . Signal Transduction and Targeted Therapy . 4 . 1 . 64 . December 24, 2019 . 31885879 . 6927964 . 10.1038/s41392-019-0101-6 . free .
  17. 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. Roots Analysis . Cision . en. May 12, 2020.
  18. Web site: Carfilzomib: The Latest Triumph of Targeted Therapies Development . Yale Scientific . November 10, 2012 . May 22, 2016.
  19. Web site: 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. April 24, 2018.
  20. Web site: The Myeloma Crowd . 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.. August 20, 2021 . en.
  21. Web site: Craig Crews, PhD. August 20, 2021. medicine.yale.edu. en.
  22. Web site: Carfilzomib: The Latest Triumph of Targeted Therapies Development – Yale Scientific Magazine . 2023-12-11 . www.yalescientific.org.
  23. Book: Development and Characterization of Proteasome Inhibitors . National Library of Medicine. 2005 . 2556561 . Kim . K. B. . Fonseca . F. N. . Crews . C. M. . Methods in Enzymology . 399 . 585–609 . 10.1016/S0076-6879(05)99039-3 . 16338383 . 978-0-12-182804-2 .
  24. Web site: Dr. Crews describes his discovery. . 2023-12-11 . healthtree.org . en.
  25. From Epoxomicin to Carfilzomib: Chemistry, Biology, and Medical Outcomes . National Library of Medicine. 2013 . 3815659 . Kim . K. B. . Crews . C. M. . 30 . 5 . 600–604 . 10.1039/c3np20126k . 23575525 .
  26. Web site: Onyx strikes $851M deal to buy Proteolix .
  27. Web site: McCaffrey . Kevin . 2013-08-26 . Kyprolis growth prospects at center of Amgen-Onyx deal . 2023-12-11 . MM+M - Medical Marketing and Media . en-US.
  28. Web site: CENTER FOR DRUG EVALUATION AND RESEARCH (PDF) .
  29. Web site: Recorded Webinar: From Kyprolis to PROTACs — Insights with Amgen's Ray Deshaies . 2023-12-11 . www.collaborativedrug.com . en.
  30. An overview of PROTACs: a promising drug discovery paradigm . 2022 . 9763089 . Liu . Z. . Hu . M. . Yang . Y. . Du . C. . Zhou . H. . Liu . C. . Chen . Y. . Fan . L. . Ma . H. . Gong . Y. . Xie . Y. . Molecular Biomedicine . 3 . 1 . 46 . 10.1186/s43556-022-00112-0 . free . 36536188 .
  31. Sakamoto . Kathleen M. . Kim . Kyung B. . Kumagai . Akiko . Mercurio . Frank . Crews . Craig M. . Deshaies . Raymond J. . 2001-07-17 . Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation . Proceedings of the National Academy of Sciences . en . 98 . 15 . 8554–8559 . 10.1073/pnas.141230798 . free . 0027-8424 . 37474 . 11438690. 2001PNAS...98.8554S .
  32. Web site: How Chemists Are Sending Bad Proteins Out With The Cellular Trash . 2023-12-11 . Chemical & Engineering News . en.
  33. Web site: Protein Degradation with PROTAC Protein Degraders . 2023-12-11 . Arvinas . en-US.
  34. Mullard . Asher . 2019-11-06 . Arvinas's PROTACs pass first safety and PK analysis . Nature Reviews Drug Discovery . en . 18 . 12 . 895 . 10.1038/d41573-019-00188-4. 31780851 .
  35. Web site: Pioneering the future of targeted protein degradation therapeutics (PDF) .
  36. Web site: Arvinas and Pfizer Announce Global Collaboration to Develop and Commercialize PROTAC® Protein Degrader ARV-471 Pfizer . 2023-12-11 . www.pfizer.com.
  37. Web site: 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. Web site: 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. Web site: Craig Martine Crews (PDF) .
  40. Web site: Halda emerges from stealth with bifunctional molecules to treat cancer . 2023-12-11 . Chemical & Engineering News . en.
  41. Web site: Siduma Therapeutics . 2023-12-11 . Siduma Therapeutics . en-US.
  42. Web site: Profile . 2023-12-11 . www.humboldt-foundation.de . en.
  43. Web site: Leadership . 2023-12-11 . Arvinas . en-US.
  44. Web site: 2014-08-18 . Crews awarded UCB-Ehrlich Award for work on anti-cancer therapy . 2023-12-11 . YaleNews . en.
  45. Web site: Agnew . Vicky . Craig Crews, PhD, receives NCI's Outstanding Investigator Award . 2023-12-11 . medicine.yale.edu . en.
  46. Web site: Craig M. Crews, PhD receives the Yale Cancer Center Translational Research Prize . 2023-12-11 . www.yalecancercenter.org . en.
  47. Web site: 2017-02-28 . Yale's Craig Crews is recipient of cancer research award . 2023-12-11 . YaleNews . en.
  48. Web site: Chemistry Biology Interface open prize: Khorana Prize . 2023-12-11 . Royal Society of Chemistry . en-GB.
  49. Web site: Craig Crews receives 2018 Pierre Fabre Award for Therapeutic Innovation Department of Chemistry . 2023-12-11 . chem.yale.edu.
  50. Web site: 2019 Award Winners . 2023-12-11 . www . en.
  51. Web site: Craig Crews Department of Chemistry . 2023-12-11 . chem.yale.edu . en.
  52. Web site: 2020: Professor Dr Craig M. Crews - Heinrich Wieland Prize - Homepage . 2023-12-11 . www.heinrich-wieland-prize.de.
  53. Web site: Awards & Honors . 2023-12-11 . www.yalecancercenter.org . en.
  54. Web site: Hathaway . Bill . 2022-05-16 . Yale scientist receives Connecticut Medal of Technology for pioneering work . 2023-12-11 . YaleNews . en.
  55. Web site: Scientists Craig Crews and Raymond Deshaies selected for Gabbay Award . 2023-12-11 . BrandeisNOW . en.
  56. Web site: Bristol Myers Squibb Award in Enzyme Chemistry – Division of Biological Chemistry . 2023-12-11 . en-US.

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