Craig M. Crews | |
---|---|
Born | June 1, 1964 59) | (age
Alma mater | University of Virginia Harvard University |
Known for | Proteolysis Targeting Chimeras (PROTACs) Controlled Proteostasis Carfilzomib |
Awards | 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) |
Scientific career | |
Fields | Chemical Biology |
Institutions | Yale University |
Doctoral advisors | Raymond 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]
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]
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]
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]
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]
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.
Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins. They are being studied in the treatment of cancer; three are approved for use in treating multiple myeloma.
Stuart Schreiber, Ph.D. is the Morris Loeb Research Professor at Harvard University, a co-Founder of the Broad Institute, Howard Hughes Medical Institute Investigator, Emeritus, and a member of the National Academy of Sciences and National Academy of Medicine. He currently leads Arena BioWorks.
Proteolix, Inc., was a private biotechnology company with headquarters in South San Francisco, California. Proteolix was founded in 2003 based on technology developed by co-founders Dr. Craig Crews and Dr. Raymond J. Deshaies. Drs. Susan Molineaux and Phil Whitcome (deceased) joined Drs. Crews and Deshaies as co-founders. Proteolix was launched based on an $18.2 million A round comprising investments by Latterell Venture Partners, US Venture Partners, Advanced Technology Ventures, and The Vertical Group. Proteolix focused primarily on the proteasome as a therapeutic target. Its lead product candidate, carfilzomib (PR-171), is a tetrapeptide epoxyketone. At the time of its sale, the company had two earlier-stage programs, an orally-bioavailable proteasome inhibitor for oncology (PR-047), and an agent preferentially targeting the immuno form of the proteasome (PR-957), with potential utility in areas such as rheumatoid arthritis. At the time of sale, Carfilzomib's route of administration was intravenous, and the company was exploring its potential utility in multiple myeloma, Non-Hodgkin lymphoma (NHL) and other cancers.
Proteasome subunit beta type-7 as known as 20S proteasome subunit beta-2 is a protein that in humans is encoded by the PSMB7 gene.
CDC34 is a gene that in humans encodes the protein Ubiquitin-conjugating enzyme E2 R1. This protein is a member of the ubiquitin-conjugating enzyme family, which catalyzes the covalent attachment of ubiquitin to other proteins.
Nuclear factor erythroid 2-related factor 1 (Nrf1) also known as nuclear factor erythroid-2-like 1 (NFE2L1) is a protein that in humans is encoded by the NFE2L1 gene. Since NFE2L1 is referred to as Nrf1, it is often confused with nuclear respiratory factor 1 (Nrf1).
NUAK family SNF1-like kinase 1 also known as AMPK-related protein kinase 5 (ARK5) is an enzyme that in humans is encoded by the NUAK1 gene.
26S proteasome non-ATPase regulatory subunit 14, also known as 26S proteasome non-ATPase subunit Rpn11, is an enzyme that in humans is encoded by the PSMD14 gene. This protein is one of the 19 essential subunits of the complete assembled 19S proteasome complex. Nine subunits Rpn3, Rpn5, Rpn6, Rpn7, Rpn8, Rpn9, Rpn11, SEM1, and Rpn12 form the lid sub complex of the 19S regulatory particle of the proteasome complex.
Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals.
Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.
Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.
A selective estrogen receptor degrader or downregulator (SERD) is a type of drug which binds to the estrogen receptor (ER) and, in the process of doing so, causes the ER to be degraded and thus downregulated. They are used to treat estrogen receptor-sensitive or progesterone receptor-sensitive breast cancer, along with older classes of drugs like selective estrogen receptor modulators (SERMs) and aromatase inhibitors.
Definition: A small molecule having two active domains connected by a linker that increases the proximity and positive co-operativity between protein of interest (POI) and E3 Ligase by binding to both of them simultaneously, this leads to polyubiquitination of POI. The purpose of PROTACs is to achieve degradation of polyubiquitinated protein by the proteosome.
Raymond Joseph Deshaies is an American biochemist and cell biologist. He is senior vice president of global research at Amgen and a visiting associate at the California Institute of Technology (Caltech). Prior to that, he was a professor of biology at Caltech and an investigator of the Howard Hughes Medical Institute. He is also the co-founder of the biotechnology companies Proteolix and Cleave Biosciences. His research focuses on mechanisms and regulation of protein homeostasis in eukaryotic cells, with a particular focus on how proteins are conjugated with ubiquitin and degraded by the proteasome.
Alessio Ciulli is an Italian British biochemist. Currently, he is the Professor of Chemical & Structural Biology at the School of Life Sciences, University of Dundee, where he founded and directs Dundee' new Centre for Targeted Protein Degradation (CeTPD). He is also the scientific co-founder and advisor of Amphista Therapeutics.
Molecular glue refers to a class of chemical compounds or molecules that play a crucial role in binding and stabilizing protein-protein interactions in biological systems. These molecules act as "glue" by enhancing the affinity between proteins, ultimately influencing various cellular processes. Molecular glue compounds have gained significant attention in the fields of drug discovery, chemical biology, and fundamental research due to their potential to modulate protein interactions, and thus, impact various cellular pathways. They have unlocked avenues in medicine previously thought to be “undruggable.”
James Allen Wells is a Professor of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology at the University of California, San Francisco (UCSF) and a member of the National Academy of Sciences. He received his B.A. degrees in biochemistry and psychology from University of California, Berkeley in 1973 and a PhD in biochemistry from Washington State University with Ralph Yount, PhD in 1979. He completed his postdoctoral studies at Stanford University School of Medicine with George Stark in 1982. He is a pioneer in protein engineering, phage display, fragment-based lead discovery, cellular apoptosis, and the cell surface proteome.
Chimeric small molecule therapeutics are a class of drugs designed with multiple active domains to operate outside of the typical protein inhibition model. While most small molecule drugs inhibit target proteins by binding their active site, chimerics form protein-protein ternary structures to induce degradation or, less frequently, other protein modifications.