Stuart Schreiber (born February 6, 1956) is an American chemist who is the Morris Loeb Research Professor at Harvard University,[1] a co-founder of the Broad Institute,[2] Howard Hughes Medical Institute Investigator, Emeritus,[3] and a member of the National Academy of Sciences[4] and National Academy of Medicine.[5] He currently leads Arena BioWorks.
His work integrates chemical biology and human biology to advance the science of therapeutics. Key advances include the discovery that small molecules can function as “molecular glues” that promote protein–protein interactions, the co-discovery of mTOR and its role in nutrient-response signaling, the discovery of histone deacetylases and (with Michael Grunstein and David Allis) the demonstration that chromatin marks regulate gene expression, the development and application of diversity-oriented synthesis to microbial therapeutics, and the discovery of vulnerabilities of cancer cells linked to genetic, lineage and cell-state features, including ferroptotic vulnerabilities. His awards include the Wolf Prize in Chemistry and the Arthur Cope Award. His approach to discovering new therapeutics guided many biotechnology companies that he founded, including Vertex Pharmaceuticals and Ariad Pharmaceuticals. He has founded or co-founded 14 biotechnology companies, which have developed 16 first-in-human approved drugs or advanced clinical candidates.
Early life
Schreiber was born on February 6, 1956, in Eatontown, New Jersey, to Mary Geraldine Schreiber and Thomas Sewell Schreiber. From the ages of one to four he lived with his family in Villennes-sur-Seine, a small village in France, where his father was a battalion commander at Supreme Headquarters Allied Powers Europe.[6] Shortly after returning to New Jersey, they moved to Fairfax, VA, where Tom Schreiber worked as an applied mathematician and physicist at Signal Corp on Fort Monmouth. At age 61, Schreiber discovered that Tom Schreiber was not his biological father.[7]
Schreiber attended Luther Jackson Junior High School in Falls Church, VA and graduated from Oakton High School in Fairfax, VA in 1973 after completing a 3-year work study program that prepared him for work in the construction field.[8]
Education and training
Schreiber obtained a Bachelor of Science degree in chemistry from the University of Virginia in 1977, after which he entered Harvard University as a graduate student in chemistry. He joined the research group of Robert B. Woodward and after Woodward's death continued his studies under the supervision of Yoshito Kishi. In 1980, he joined the faculty of Yale University as an assistant professor in chemistry, and in 1988 he moved to Harvard University as the Morris Loeb Professor.[9]
Career
Schreiber started his research work in organic synthesis, focusing on concepts such as the use of [2 + 2] photocycloadditions to establish stereochemistry in complex molecules, the fragmentation of hydroperoxides to produce macrolides, ancillary stereocontrol, group selectivity and two-directional synthesis. Notable accomplishments include the total syntheses of complex natural products such as periplanone B, talaromycin B, asteltoxin, avenaciolide, gloeosporone, hikizimicin, mycoticin A, epoxydictymene[10] and the immunosuppressant FK-506.[citation needed]
Following his work on the FK506-binding protein FKBP12 in 1988, Schreiber reported that the small molecules FK506 and cyclosporin inhibit the activity of the phosphatase calcineurin by forming the ternary complexes FKBP12-FK506-calcineurin and cyclophilin-ciclosporin-calcineurin.[11] This work, together with work by Gerald Crabtree at Stanford University concerning the NFAT proteins, led to the elucidation of the calcium-calcineurin-NFAT signaling pathway.[12] The Ras-Raf-MAPK pathway was not elucidated for another year.[citation needed]
In 1993, Schreiber and Crabtree developed bifunctional molecules or “chemical inducers of proximity” (CIPs), which provide small-molecule activation over numerous signaling molecules and pathways (e.g., the Fas, insulin, TGFβ and T-cell receptors[13][14]) through proximity effects. Schreiber and Crabtree demonstrated that small molecules could activate a signaling pathway in an animal with temporal and spatial control.[15] Dimerizer kits have been distributed freely resulting in many peer-reviewed publications. Its promise in gene therapy has been highlighted by the ability of a small molecule to activate a small-molecule regulated EPO receptor and to induce erythropoiesis (Ariad Pharmaceuticals, Inc.), and more recently in human clinical trials for treatment of graft-vs-host disease.[16]
In 1994, Schreiber and co-workers investigated (independently with David Sabitini) the master regulator of nutrient sensing, mTOR. They found that the small molecule rapamycin simultaneously binds FKBP12 and mTOR (originally named FKBP12-rapamycin binding protein, FRAP).[17] Using diversity-oriented synthesis and small-molecule screening, Schreiber illuminated the nutrient-response signaling network involving TOR proteins in yeast and mTOR in mammalian cells. Small molecules such as uretupamine[18] and rapamycin were shown to be particularly effective in revealing the ability of proteins such as mTOR, Tor1p, Tor2p, and Ure2p to receive multiple inputs and to process them appropriately towards multiple outputs (in analogy to multi-channel processors). Several pharmaceutical companies are now targeting the nutrient-signaling network for the treatment of several forms of cancer, including solid tumors.[19]
In 1995, Schreiber and co-workers found that the small molecule lactacystin binds and inhibits specific catalytic subunits of the proteasome,[20] a protein complex responsible for the bulk of proteolysis in the cell, as well as proteolytic activation of certain protein substrates. As a non-peptidic proteasome inhibitor lactacysin has proven useful in the study of proteasome function. Lactacystin modifies the amino-terminal threonine of specific proteasome subunits. This work helped to establish the proteasome as a mechanistically novel class of protease: an amino-terminal threonine protease. The work led to the use of bortezomib to treat multiple myeloma.[citation needed]
In 1996, Schreiber and co-workers used the small molecules trapoxin and depudecin to investigate the histone deacetylases (HDACs).[21] Prior to Schreiber's work in this area, the HDAC proteins had not been isolated. Coincident with the HDAC work, David Allis and colleagues reported work on the histone acetyltransferases (HATs). These two contributions catalyzed much research in this area, eventually leading to the characterization of numerous histone-modifying enzymes, their resulting histone “marks”, and numerous proteins that bind to these marks. By taking a global approach to understanding chromatin function, Schreiber proposed a “signaling network model” of chromatin and compared it to an alternative view, the “histone code hypothesis” presented by Strahl and Allis.[22] These studies shined a bright light on chromatin as a key gene expression regulatory element rather than simply a structural element used for DNA compaction.[citation needed]
Diversity-oriented synthesis
Schreiber applied small molecules to biology through the development of diversity-oriented synthesis (DOS),[23] chemical genetics,[24] and ChemBank.[25] Schreiber has shown that DOS can produce small molecules distributed in defined ways in chemical space by virtue of their different skeletons and stereochemistry, and that it can provide chemical handles on products anticipating the need for follow-up chemistry using, for example, combinatorial synthesis and the so-called Build/Couple/Pair strategy of modular chemical synthesis. DOS pathways and new techniques for small-molecule screening [26][27][28] provided many new, potentially disruptive insights into biology. Small-molecule probes of histone and tubulin deacetylases, transcription factors, cytoplasmic anchoring proteins, developmental signaling proteins (e.g., histacin, tubacin, haptamide, uretupamine, concentramide, and calmodulophilin), among many others, have been uncovered in the Schreiber lab using diversity-oriented synthesis and chemical genetics. Multidimensional screening was introduced in 2002 and has provided insights into tumorigenesis, cell polarity, and chemical space, among others.[29]
Using diversity-oriented synthesis, the Schreiber Lab and collaborators discovered numerous novel antimicrobial compounds including the bicyclic azetidine BRD7929 that could both cure and prevent the transmission of malaria in mice, targeting multiple steps in the life cycle of Plasmodium falciparum.[30][31] They found another synthetic azetidine derivative, BRD4592, which kills Mycobacterium tuberculosis through allosteric inhibition of its tryptophan synthase.[32] High throughput screens further uncovered compounds that inhibit replication of Trypanosoma cruzi[33] and Hepatitis C virus,[34][35] and inhibit Toxoplasma gondii growth.[36]
Other research
Schreiber also contributed to more conventional small molecule discovery projects. He collaborated with Tim Mitchison to discover monastrol – the first small-molecule inhibitor of mitosis that does not target tubulin.[37]Monastrol was shown to inhibit kinesin-5, a motor protein and was used to gain new insights into the functions of kinesin-5. This work led pharmaceutical company Merck, among others, to pursue anti-cancer drugs that target human kinesin-5.[citation needed]
Recently[when?] the Schreiber Lab discovered that when certain aggressive cancer cells become resistant to drug treatments, they also become vulnerable to ferroptosis—a natural cellular self-destruction mechanism triggered by peroxide and iron ions undergoing the Fenton reaction. Free radicals unleash a chain reaction turning normal lipids in the cell membrane into toxic radical species. They found that drug-resistant cancer cells that have acquired this new vulnerability rely on an enzyme called GPX4 for survival. GPX4 stops the chain reaction leading to ferroptosis by converting the dangerous lipid peroxides to benign alcohols. They further showed that a small molecule inhibitor of GPX4 kills cancer cells by increasing their vulnerability to ferroptosis.[38]
Impact on chemical biology
Schreiber has used small molecules to study three specific areas of biology, and then through the more general application of small molecules in biomedical research. Academic screening centers have been created that emulate the Harvard Institute of Chemistry and Cell Biology and the Broad Institute; in the U.S., there has been a nationwide effort to expand this capability via the government-sponsored NIH Road Map. Chemistry departments have changed their names to include the term chemical biology and new journals have been introduced (Cell Chemical Biology, ChemBioChem, Nature Chemical Biology, ACS Chemical Biology]) to cover the field. Schreiber has been involved in the founding of numerous biopharmaceutical companies whose research relies on chemical biology: Vertex Pharmaceuticals, Inc. (VRTX), Ariad Pharmaceuticals, Inc. (ARIA), Infinity Pharmaceuticals, Inc (INFI), Forma Therapeutics, H3 Biomedicine, Jnana Therapeutics, and Kojin Therapeutics. These companies have produced new therapeutics in several disease areas, including cystic fibrosis and cancer.[39]
↑ Schreiber, Stuart L. (July–August 2019). "Truth: A Love Story". Harvard Magazine. Retrieved November 29, 2023.
↑ Werth, Barry (1994). The Billion Dollar Molecule: One Company's quest for the perfect drug. United States of America: Simon & Schuster. pp.197–198. ISBN978-0671510572.
↑ Jamison, Timothy F.; Shambayati, Soroosh; Crowe, William E.; Schreiber, Stuart L. (1994-06-01). "Cobalt-Mediated Total Synthesis of (+)-Epoxydictymene". Journal of the American Chemical Society. 116 (12): 5505–5506. doi:10.1021/ja00091a079. ISSN0002-7863.
↑ Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL (August 1991). "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes". Cell. 66 (4): 807–15. doi:10.1016/0092-8674(91)90124-H. PMID1715244. S2CID22094672.
↑ Schreiber SL, Crabtree GR (1995). "Immunophilins, ligands, and the control of signal transduction". Harvey Lectures. 91: 99–114. PMID9127988.
↑ "Functional Analysis of Fas Signaling in vivo Using Synthetic Dimerizers" David Spencer, Pete Belshaw, Lei Chen, Steffan Ho, Filippo Randazzo, Gerald R. Crabtree, Stuart L. Schreiber Curr. Biol. 1996, 6, 839–848.
↑ "Dissection of a glucose-sensitive pathway of the nutrient-response network using diversity-oriented synthesis and small molecule microarrays" Finny G. Kuruvilla, Alykhan F. Shamji, Scott M. Sternson, Paul J. Hergenrother, Stuart L. Schreiber, Nature, 2002, 416, 653–656.
↑ "The small-molecule approach to biology: Chemical genetics and diversity-oriented organic synthesis make possible the systematic exploration of biology”, S L Schreiber, C&E News, 2003, 81, 51–61.
↑ "Printing Small Molecules as Microarrays and Detecting Protein-Ligand Interactions en Masse" Gavin MacBeath, Angela N. Koehler, Stuart L. Schreiber J. Am. Chem. Soc.1999, 121, 7967–7968.
Proteasomes are protein complexes which degrade ubiquitin-tagged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Ubiquitin is a small (8.6 kDa) 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.
Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.
Chemical biology is a scientific discipline between the fields of chemistry and biology. The discipline involves the application of chemical techniques, analysis, and often small molecules produced through synthetic chemistry, to the study and manipulation of biological systems. Although often confused with biochemistry, which studies the chemistry of biomolecules and regulation of biochemical pathways within and between cells, chemical biology remains distinct by focusing on the application of chemical tools to address biological questions.
A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the N-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. Their affinity is higher for regions where multiple acetylation sites exist in proximity. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.
Lactacystin is an organic compound naturally synthesized by bacteria of the genus Streptomyces first identified as an inducer of neuritogenesis in neuroblastoma cells in 1991. The target of lactacystin was subsequently found to be the proteasome on the basis of its affinity for certain catalytic subunits of the proteasome by Fenteany and co-workers in 1995. The proteasome is a protein complex responsible for the bulk of proteolysis in the cell, as well as proteolytic activation of certain protein substrates. Lactacystin was the first non-peptidic proteasome inhibitor discovered and is widely used as a research tool in biochemistry and cell biology. The transformation product of lactacystin clasto-lactacystin β-lactone covalently modifies the amino-terminal threonine of specific catalytic subunits of the proteasome, a discovery that helped to establish the proteasome as a mechanistically novel class of protease: an amino-terminal threonine protease. The molecule is commonly used in biochemistry and cell biology laboratories as a selective inhibitor of the proteasome. The first total synthesis of lactacystin was developed in 1992 by Corey and Reichard, and a number of other syntheses of this molecule have also been published. There are more than 1,660 entries for lactacystin in PubMed as of January 2019.
ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.
Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the SIN3A gene.
Peptidyl-prolyl cis-trans isomerase FKBP1A is an enzyme that in humans is encoded by the FKBP1A gene. It is also commonly referred to as FKBP-12 or FKBP12 and is a member of a family of FK506-binding proteins (FKBPs).
Calcineurin-binding protein cabin-1 is a protein that in humans is encoded by the CABIN1 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.
MG132 is a potent, reversible, and cell-permeable proteasome inhibitor (Ki = 4 nM). It belongs to the class of synthetic peptide aldehydes. It reduces the degradation of ubiquitin-conjugated proteins in mammalian cells and permeable strains of yeast by the 26S complex without affecting its ATPase or isopeptidase activities. MG132 activates c-Jun N-terminal kinase (JNK1), which initiates apoptosis. MG132 also inhibits NF-κB activation with an IC50 of 3 μM and prevents β-secretase cleavage.
Laura Lee Kiessling is an American chemist and the Novartis Professor of Chemistry at the Massachusetts Institute of Technology. Kiessling's research focuses on elucidating and exploiting interactions on the cell surface, especially those mediated by proteins binding to carbohydrates. Multivalent protein-carbohydrate interactions play roles in cell-cell recognition and signal transduction. Understanding and manipulating these interactions provides tools to study biological processes and design therapeutic treatments. Kiessling's interdisciplinary research combines organic synthesis, polymer chemistry, structural biology, and molecular and cell biology.
Gerald R. Crabtree is the David Korn Professor at Stanford University and an Investigator in the Howard Hughes Medical Institute. He is known for defining the Ca2+-calcineurin-NFAT signaling pathway, pioneering the development of synthetic ligands for regulation of biologic processes and discovering chromatin regulatory mechanisms involved in cancer and brain development. He is a founder of Ariad Pharmaceuticals, Amplyx Pharmaceuticals, Foghorn Therapeutics, and Shenandoah Therapeutics.
A stapled peptide is a modified peptide, typically in an alpha-helical conformation, that is constrained by a synthetic brace ("staple"). The staple is formed by a covalent linkage between two amino acid side-chains, forming a peptide macrocycle. Staples, generally speaking, refer to a covalent linkage of two previously independent entities. Peptides with multiple, tandem staples are sometimes referred to as stitched peptides. Among other applications, peptide stapling is notably used to enhance the pharmacologic performance of peptides.
Craig M. Crews 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. 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.
A proteolysis targeting chimera (PROTAC) is a molecule that can remove specific unwanted proteins. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing selective intracellular proteolysis. A heterobifunctional molecule with two active domains and a linker, PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to a target protein meant for degradation. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome. Because PROTACs need only to bind their targets with high selectivity, there are currently many efforts to retool previously ineffective inhibitor molecules as PROTACs for next-generation drugs.
FK1012 is a dimer consisting of two molecules of tacrolimus (FK506) linked via their vinyl groups. It is used as a research tool in chemically induced dimerization applications. FK1012 is a chemical inducer of dimerization (CID) which makes the protein capable of dimerization or oligomerization of fusion proteins containing one or more FKBP12 domains. It is used in pharmacology to act as a mediator in the formation of FK506 dimer. FK506 binding proteins (FKBPs) do not normally form dimers but can be caused to dimerize in the presence of FK1012. Genetically engineered proteins based on FKBPs can be used to manipulate protein localization, signaling pathways and protein activation.
The bump-and-hole method is a tool in chemical genetics for studying a specific isoform in a protein family without perturbing the other members of the family. The unattainability of isoform-selective inhibition due to structural homology in protein families is a major challenge of chemical genetics. With the bump-and-hole approach, a protein–ligand interface is engineered to achieve selectivity through steric complementarity while maintaining biochemical competence and orthogonality to the wild type pair. Typically, a "bumped" ligand/inhibitor analog is designed to bind a corresponding "hole-modified" protein. Bumped ligands are commonly bulkier derivatives of a cofactor of the target protein. Hole-modified proteins are recombinantly expressed with an amino acid substitution from a larger to smaller residue, e.g. glycine or alanine, at the cofactor binding site. The designed ligand/inhibitor has specificity for the engineered protein due to steric complementarity, but not the native counterpart due to steric interference.
Angela N. Koehler is an American biochemist who is the Karl Van Tassel (1925) Career Development Professor of Chemical Biology at the Broad Institute. Her research considers the development of chemical tools to understand transcriptional regulation, and the design of next-generation pharmaceuticals.
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