Masters of Molecular Design
How Nicolaou and Schreiber Transformed Chemistry
Wolf Prize 2016
Shared by both scientistsInstitutions
Rice University & HarvardTherapeutics
Taxol, Rapamycin, VorinostatThe Nobel's Crystal Ball: A Prize That Predicts Future Legends
In the world of science, few honors carry the weight of the Wolf Prize—an award so prestigious that it often serves as a precursor to the Nobel Prize. When the 2016 Wolf Prize in Chemistry was announced, it recognized two extraordinary scientists whose work had fundamentally expanded chemistry's frontiers: Kyriacos Costa Nicolaou of Rice University and Stuart L. Schreiber of Harvard University 1 .
Together, they exemplified how chemistry serves as a bridge between the molecular world and medical innovation. Their approaches—once considered separate domains of chemistry and biology—have converged into the integrated field of chemical biology, which now stands at the forefront of therapeutic discovery and development.
K.C. Nicolaou: The Master Builder
Kyriacos Costa Nicolaou, born in Cyprus and educated in London before moving to the United States, has dedicated his career to achieving what many considered impossible: the total synthesis of extraordinarily complex natural products. His work focuses on pushing synthetic chemistry "to the extremes of molecular complexity," linking structure and function across the interfaces of chemistry, biology, and medicine 1 3 .
Nicolaou is perhaps best known for publishing the first complete synthetic pathway to Taxol (paclitaxel), a potent chemotherapeutic drug used to treat ovarian, breast, lung, pancreatic, and other cancers 3 9 . This remarkable achievement, completed alongside Robert A. Holton's nearly simultaneous synthesis, represented a triumph of organic synthesis given Taxol's intricate molecular architecture.
Beyond Taxol, Nicolaou's research group has successfully synthesized numerous other complex molecules, including the immunosuppressant rapamycin and the antibiotic vancomycin 2 . His syntheses have not only provided access to scarce natural products but have also generated analogs with improved pharmaceutical properties, created new methodologies for chemical synthesis, and offered profound insights into molecular structure and function 1 3 .
Key Achievements
- Total synthesis of Taxol
- Synthesis of rapamycin
- Synthesis of vancomycin
- Marine biotoxin synthesis
Taxol (Paclitaxel)
A potent chemotherapeutic agent with a highly complex molecular architecture. Nicolaou's synthesis provided access to this scarce natural product and enabled the creation of analogs with improved properties 3 9 .
Vancomycin
A challenging antibiotic synthesis that addressed a molecule with multiple delicate functional groups requiring precise spatial arrangement 2 .
Rapamycin
An immunosuppressant with a complex macrocyclic structure. Its synthesis represented a milestone in the field of total synthesis 2 .
Marine Biotoxins
Complex structures presenting unique challenges due to their elaborate polyether networks 1 .
Stuart L. Schreiber: The Chemical Decoder
Stuart L. Schreiber, a Harvard professor and director at the Broad Institute, pioneered the field of chemical biology and developed innovative approaches to understanding cellular processes. His work earned him the Wolf Prize for "pioneering chemical insights into the logic of signal transduction and gene regulation that led to important new therapeutics, and for advancing chemical biology and medicine through the discovery of small-molecule probes" 1 8 .
Schreiber's research has led to fundamental discoveries about how cells communicate and process information. His work on the FK506-binding protein FKBP12 in 1988, combined with his colleague Gerald Crabtree's discovery of NFAT proteins, led to the complete elucidation of the calcium-calcineurin-NFAT signaling pathway—the first comprehensive mapping of an entire cellular signaling pathway from the cell surface to the nucleus 6 . This breakthrough established a new paradigm for understanding intracellular communication.
Schreiber's research has directly contributed to developing therapeutic agents including temsirolimus and vorinostat, and has provided tools that hundreds of laboratories worldwide use to explore cellular function 2 6 .
Key Contributions
- Mapping signaling pathways
- Diversity-oriented synthesis
- Histone deacetylase discovery
- "Bump-and-hole" strategy
Chemical Genetic Tools
Development of innovative methods like the "bump-and-hole" strategy that enable precise control of specific protein functions within complex cellular environments.
Two Paths, One Destination: Revolutionizing Science and Medicine
Total synthesis represents one of organic chemistry's most demanding disciplines, requiring the construction of complex natural molecules entirely through laboratory methods. Nicolaou's approach has consistently targeted molecules of extraordinary architectural complexity and medical significance:
- Taxol: His synthesis of this anticancer agent required developing innovative methods to assemble its intricate core structure 3 9 .
- Vancomycin: This challenging antibiotic synthesis addressed a molecule with multiple delicate functional groups that demanded precise spatial arrangement 2 .
- Marine biotoxins: These complex structures present unique challenges due to their elaborate polyether networks 1 .
Schreiber's work harnesses small molecules as probes to investigate biological systems—an approach now fundamental to modern chemical biology. His key contributions include:
- Mapping signaling pathways: His work illuminated how information travels within cells, particularly through the mTOR pathway that regulates cell growth, proliferation, and survival 6 8 .
- Pioneering diversity-oriented synthesis (DOS): This innovative approach creates structurally diverse compound libraries for biological screening 6 8 .
- Discovering histone deacetylases (HDACs): Revealed chromatin as a dynamic regulatory element, fundamentally advancing epigenetics 6 8 .
| Scientist | Key Discoveries/Innovations | Resulting Therapeutics | Medical Applications |
|---|---|---|---|
| K.C. Nicolaou | Total synthesis of Taxol | Paclitaxel | Ovarian, breast, lung, pancreatic cancers |
| Synthesis of rapamycin | Immunosuppressants | Organ transplantation | |
| Synthesis of vancomycin | Antibiotic analogs | Drug-resistant infections | |
| Stuart L. Schreiber | Elucidation of mTOR pathway | Temsirolimus | Renal cell carcinoma |
| Discovery of HDAC mechanisms | Vorinostat, Romidepsin | Cutaneous T-cell lymphoma | |
| Calcium-calcineurin-NFAT pathway | FK506 (tacrolimus) | Organ transplantation |
Inside the Lab: The "Bump-and-Hole" Strategy
One of Schreiber's most ingenious methodological contributions is the "bump-and-hole" approach—a chemical genetic strategy that enables precise control of specific protein functions within complex cellular environments.
This innovative technique involves several key steps:
- Engineering the Protein Target: Scientists first modify a protein of interest to create a small cavity or "hole" near its active site through targeted mutagenesis.
- Designing Complementary Ligands: Researchers then design synthetic small molecules ("probes") containing a strategic bulky extension or "bump" that sterically fits only the engineered binding pocket.
- Creating Specificity: The engineered small molecule binds exclusively to the engineered protein, not the wild-type version, allowing researchers to selectively manipulate specific protein functions without affecting similar proteins in the cell.
- Biological Investigation: Using this matched pair, scientists can probe the function of individual proteins in complex biological pathways with unprecedented precision.
The bump-and-hole strategy represents a powerful approach for target validation in drug discovery and has been widely adopted to study protein families where members have overlapping functions, such as kinases, proteases, and GTPases.
This method allows researchers to dissect the specific contributions of individual proteins to complex cellular phenotypes, bridging the gap between genetic and small-molecule approaches to understanding biological systems 8 .
Key Advantage
Enables selective manipulation of specific protein functions without affecting similar proteins in the cell.
| Research Tool | Function | Application Examples |
|---|---|---|
| Small-molecule probes | Selective binding and modulation of protein function | FK506 for immunosuppression studies; trapoxin for HDAC isolation |
| Diversity-Oriented Synthesis (DOS) libraries | Generation of structurally diverse compounds for screening | Discovery of novel probes for previously "undruggable" targets |
| "Bump-and-hole" systems | Engine protein-small molecule pairs for precise manipulation | Studying specific kinase functions in signal transduction |
| Natural product isolates | Bioactive compounds from natural sources | Starting points for total synthesis and drug development |
| Synthetic analogs | Modified versions of natural products | Improving pharmaceutical properties; probing structure-activity relationships |
The Wolf Prize: Recognizing Excellence Beyond the Nobel
The Wolf Foundation, established by German-born inventor and former Cuban ambassador to Israel Ricardo Wolf, has presented these international awards since 1978. The prizes honor outstanding achievements in agriculture, chemistry, mathematics, medicine, physics, and the arts "in the interest of mankind and friendly relations among people" 1 5 .
The Wolf Prize in Chemistry is widely considered second only to the Nobel Prize in prestige, with approximately one-third of Wolf chemistry laureates eventually receiving the Nobel Prize 4 7 9 . This trend underscores the Wolf Committee's remarkable ability to identify transformative science with lasting impact.
Nicolaou and Schreiber received their awards during an official ceremony at the Knesset (Israel's parliament) in Jerusalem in June 2016, where they shared a $100,000 prize 1 2 .
| Scientist | Wolf Prize Year | Nobel Prize Year | Research Area |
|---|---|---|---|
| John C. Polanyi | 1982 | 1986 | Reaction dynamics |
| Rudolph A. Marcus | 1984/5 | 1992 | Electron transfer reactions |
| Robert H. Grubbs | 2008 | 2005 | Olefin metathesis |
| Ada Yonath | 2006/7 | 2009 | Ribosome structure |
| Akira Suzuki | 2010 | 2010 | Palladium-catalyzed cross-couplings |
| Carolyn Bertozzi | 2022 | 2022 | Click chemistry and bioorthogonal chemistry |
Chemistry's Expanding Frontier: From Molecular Synthesis to Cellular Control
The 2016 Wolf Prize in Chemistry celebrated two distinct yet complementary approaches to advancing chemical science. Nicolaou's work demonstrates how mastering molecular construction enables us to access and optimize nature's most sophisticated therapeutic agents. Simultaneously, Schreiber's research shows how small molecules can illuminate biology's deepest mysteries, revealing cellular pathways and regulatory mechanisms that can be targeted for therapeutic benefit.
Molecular Construction
Accessing and optimizing nature's most sophisticated therapeutic agents through total synthesis.
Biological Exploration
Using small molecules to illuminate cellular pathways and regulatory mechanisms.