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Seth Cohen - UC San Diego. La Jolla, CA, US

Seth Cohen Seth Cohen

Professor | UC San Diego

La Jolla, CA, UNITED STATES

Seth Cohen's research and experience include drug development, advance materials, and science policy.

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Biography

Cohen attended Stanford University where he obtained a Bachelor of Science degree in chemistry and a Bachelor of Arts degree in political science. Upon completion of his undergraduate education he moved to the University of California, Berkeley where he studied under the guidance of Kenneth N. Raymond. After completing his Ph.D. at U.C. Berkeley, he moved to Boston, to perform postdoctoral research in the laboratory of Stephen J. Lippard at the Massachusetts Institute of Technology. After about two and a half years in Boston he moved to his present position at UC San Diego. On July 1, 2011, he was promoted to the position of professor, and served as chair of the Department of Chemistry and Biochemistry at UC San Diego from July 2012 to June 2015.

Areas of Expertise (8)

Drug Discovery

Metal Organic Frameworks

Bioinorganic Chemistry

Synthesis

Inorganic Chemistry

Materials

Medicinal Chemistry

Science Policy

Accomplishments (5)

Freeman Lecturer, University of Sydney

2018

TREE Award, Research Corporation for Scientific Advancement

2017

Chancellor's Award for Excellence in Postdoctoral Mentoring

2017

Arthur C. Cope Scholar Award, American Chemical Society

2016

Leslie E. Orgel Faculty Scholar

2015

Education (3)

University of California, Berkeley: Ph.D., Chemistry 1998

Stanford University: B.S., Chemistry 1994

Stanford University: B.A., Political Science 1994

Media Appearances (3)

Getting a better grasp of manganese to fight flu

Chemistry World  

2018-03-22

Cohen says that the way to tackle flu is by targeting one of its metalloenzymes. With it knocked out, the virus can’t hijack human cells to replicate. Although flu can evade many treatments through rapid mutations, this enzyme stays the same across all influenza strains. After screening around 300 different structures Cohen’s team thought they had found a potent candidate. It wasn’t until they saw a crystal structure of their best pick in action that they realised something was amiss: the compound only bound to one of the two manganese atoms in the viral enzyme’s active site.

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New UCSD flu discovery could block illness entirely

San Diego Tribune  

2018-03-20

Seth Cohen, a UCSD professor and co-founder of San Diego’s Forge Therapeutics, said the drug inhibits a critical viral enzyme by jamming molecular machinery common to all strains. It could reduce the flu’s severity or perhaps block it completely. The drug blocks an enzyme containing the metal manganese. Such metalloenzymes form the basis of Forge’s technology, which is currently directed toward developing antibiotics, not antivirals. “This enzyme is a component that allows the virus to steal the cellular machinery, so that the virus can reproduce using the human cells,” Cohen said. The drug interrupts this process by binding to the manganese ions.

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Anti-flu drug exploits weakness in H3N2 strain

FierceBiotech  

2018-03-19

“This enzyme is completely ubiquitous across all flu strains,” said Seth Cohen, Ph.D., a professor at UCSD, during a press conference at the ACS event Monday. He believes the drug could eliminate the virus or at least slow its reproduction enough so the immune system can take over and eliminate it. Cohen is also co-founder of Forge Therapeutics, a company developing drugs that target metalloenzymes...

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Articles (5)

Understanding the origins of metal-organic framework/polymer compatibility. Chemical ScienceF

Semino R, Moreton JC, Ramsahye NA, Cohen SM, Maurin G

2018 The microscopic interfacial structures for a series of metal-organic framework/polymer composites consisting of the Zr-based UiO-66 coupled with different polymers are systematically explored by applying a computational methodology that integrates density functional theory calculations and force field-based molecular dynamics simulations. These predictions are correlated with experimental findings to unravel the structure-compatibility relationship of the MOF/polymer pairs. The relative contributions of the intermolecular MOF/polymer interactions and the flexibility/rigidity of the polymer with respect to the microscopic structure of the interface are rationalized, and their impact on the compatibility of the two components in the resulting composite is discussed. The most compatible pairs among those investigated involve more flexible polymers, i.e. polyvinylidene fluoride (PVDF) and polyethylene glycol (PEG). These polymers exhibit an enhanced contact surface, due to a better adaptation of their configuration to the MOF surface. In these cases, the irregularities at the MOF surface are filled by the polymer, and even some penetration of the terminal groups of the polymer into the pores of the MOF can be observed. As a result, the affinity between the MOF and the polymer is very high; however, the pores of the MOF may be sterically blocked due to the strong MOF/polymer interactions, as evidenced by UiO-66/PEG composites. In contrast, composites involving polymers that exhibit higher rigidity, such as the polymer of intrinsic microporosity-1 (PIM-1) or polystyrene (PS), present interfacial microvoids that contribute to a decrease in the contact surface between the two components, thus reducing the MOF/polymer affinity.

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Metal-Binding Isosteres as New Scaffolds for Metalloenzyme Inhibitors Inorganic ChemistryF

Dick BL, Cohen SM

2018 The principle of isosteres or bioisosteres in medicinal chemistry is a central and essential concept in modern drug discovery. For example, carboxylic acids are often replaced by bioisosteres to mitigate issues related to lipophilicity or acidity while retaining acidic characteristics in addition to hydrogen bond donor/acceptor abilities. Separately, the development of metal-binding pharmacophores (MBPs) for binding to the active site metal ion in metalloenzymes of therapeutic interest is an emerging area in the realm of fragment-based drug discovery (FBDD). The direct application of the bioisostere concept to MBPs has not been well-described or systematically investigated. Herein, the picolinic acid MBP is used as a case study for the development of MBP isosteres (so-called MBIs). Many of these isosteres are novel compounds, and data on their physicochemical properties, metal binding capacity, and metalloenzyme inhibition characteristics are presented. The results show that MBIs of picolinic acid generally retain metal coordinating properties and exhibit predictable metalloenzyme inhibitory activity while possessing a broad range of physicochemical properties (e.g., p Ka, log P). These findings demonstrate the use of bioisosteres results in an untapped source of metal binding functional groups suitable for metalloenzyme FBDD. These MBIs provide a previously unexplored route for modulating the physicochemical properties of metalloenzyme inhibitors and improving their drug-likeness.

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A Metal-Organic Framework with Exceptional Activity for C-H Bond Amination. Angewandte Chemie International EditionF

Wang L, Agnew DW, Yu X,Figueroa JS, Cohen SM

2018 The development of catalysts capable of fast, robust C-H bond amination under mild conditions is an unrealized goal despite substantial progress in the field of C-H activation in recent years. A Mn-based metal-organic framework (CPF-5) is described that promotes the direct amination of C-H bonds with exceptional activity. CPF-5 is capable of functionalizing C-H bonds in an intermolecular fashion with unrivaled catalytic stability producing >105 turnovers.

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Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11. Nature Chemical BiologyF

Li J,Yakushi T, Parlati F,Mackinnon AL, Perez C, Ma Y, Carter KP, Colayco S, Magnuson G, Brown B, Nguyen K, Vasile S, Suyama E, Smith LH, Sergienko E, Pinkerton AB, Chung TDY, Palmer AE, Pass I, Hess S, Cohen SM, Deshaies RJ

2017 The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.

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The Postsynthetic Renaissance in Porous Solids. Journal of the American Chemical SocietyF

Cohen SM

2017 Metal-organic frameworks (MOFs) have rapidly grown into a major area of chemical research over the last two decades. MOFs represent the development of covalent chemistry "beyond the molecule" and into extended structures. MOFs also present an unprecedented scaffold for performing heterogeneous organic transformations in the solid state, allowing for deliberate and precise preparation of new materials. The development of these transformations has given rise to the "postsynthetic renaissance", a suite of methods by which these materials can be transformed in a single-crystal-to-single-crystal manner. Postsynthetic modification, postsynthetic deprotection, postsynthetic exchange, postsynthetic insertion, and postsynthetic polymerization have exploited the unique features of both the organic and inorganic components of MOFs to create crystalline, porous solids of unique complexity and functionality.

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