Dana Ferraris

Bio: Dana Ferraris is an academic researcher from McDaniel College. The author has contributed to research in topics: Enantioselective synthesis & Alkylation. The author has an hindex of 29, co-authored 76 publications receiving 4302 citations. Previous affiliations of Dana Ferraris include Eisai & Johns Hopkins University.

Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1.

Abstract: Mutation at the R132 residue of isocitrate dehydrogenase 1 (IDH1), frequently found in gliomas and acute myelogenous leukemia, creates a neoenzyme that produces 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG). We sought to therapeutically exploit this neoreaction in mutant IDH1 cells that require α-KG derived from glutamine. Glutamine is converted to glutamate by glutaminase and further metabolized to α-KG. Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1. Growth suppression of mutant IDH1 cells by BPTES was rescued by adding exogenous α-KG. BPTES inhibited glutaminase activity, lowered glutamate and α-KG levels, and increased glycolytic intermediates while leaving total 2-HG levels unaffected. The ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggests a unique reprogramming of intermediary metabolism and a potential therapeutic strategy. Cancer Res; 70(22); 8981–7. ©2010 AACR.

The Development of the First Catalyzed Reaction of Ketenes and Imines: Catalytic, Asymmetric Synthesis of β-Lactams

Abstract: We report practical methodology for the catalytic, asymmetric synthesis of β-lactams resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines. The products of these asymmetric reactions can serve as precursors to a number of enzyme inhibitors and drug candidates as well as valuable synthetic intermediates. We present a detailed study of the mechanism of the β-lactam forming reaction with proton sponge as the stoichiometric base, including kinetics and isotopic labeling studies. Stereochemical models based on molecular mechanics (MM) calculations are also presented to account for the observed stereoregular sense of induction in our reactions and to provide a guidepost for the design of other catalyst systems.

Evolution of Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to Clinic

Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) has been an actively pursued drug discovery target for almost 3 decades. Often referred to as the “guardian angel of DNA”, this abundant nuclear enzyme has been the focus of over 20 medicinal chemistry programs in a wide range of therapeutic areas encompassing stroke, cardiac ischemia, cancer, inflammation, anddiabetes (Figure 1).Despite the great therapeutic potential for this target and the tremendous academic and industrial efforts dedicated to it, only recently have PARP-1 inhibitors made headway in clinical trials. Recent results from several PARP-1 inhibitors in phase II clinical trials for cancer therapyhave attracted the attentionofnationalmedia.Of the several potential therapeutic indications for PARP-1 inhibitors, the two major areas that hold the most promise are ischemia and cancer. This review is structured to provide the readers with a brief summary of the rationale for PARP-1 as a therapeutic target, to explain the PARP-1 inhibitor pharmacophore, and to provide an update on the progress of the PARP-1 drug discovery programs. This Perspective will offer a historical account of the critical PARP-1 publications that instilled the interest of the biopharmaceutical industry in the late 1980s and early 1990s. Furthermore, I will discuss why PARP-1 received somuch attention in the late 1990s and early 2000s followed by the slight decline in themedicinal chemistry efforts today (Figure 1). The major PARP-1 medicinal chemistry programs will be highlighted focusing on the lead generation, lead optimization, candidate selection, and clinical progress.Many aspects of the biological functions of PARP-1 fall outside the scope of this medicinal chemistry review. For this reason, the reader should refer to the following citations for a review of the PARP family of enzymes, the biological functions of poly(ADP-ribose), PARP-1 and intracellular signaling, PARP and DNA repair, PARP and epigenetics, PARP and angiogenesis, and the role of PARP-1 in inflammation. The 30 years of medicinal chemistry on this topic have also afforded some excellent medicinal chemistry reviews, most of which predated the disclosure of clinical candidate structures and recent clinical trial results.

Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES)

Abstract: The release of GA (mitochondrial glutaminase) from neurons following acute ischaemia or during chronic neurodegenerative diseases may contribute to the propagation of glutamate excitotoxicity. Thus an inhibitor that selectively inactivates the released GA may limit the accumulation of excess glutamate and minimize the loss of neurological function that accompanies brain injury. The present study examines the mechanism of inactivation of rat KGA (kidney GA isoform) by the small-molecule inhibitor BPTES [bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide]. BPTES is a potent inhibitor of KGA, but not of the liver GA isoform, glutamate dehydrogenase or γ-glutamyl transpeptidase. Kinetic studies indicate that, with respect to glutamine, BPTES has a Ki of approx. 3 μM. Moreover, these studies suggest that BPTES inhibits the allosteric activation caused by phosphate binding and promotes the formation of an inactive complex. Gel-filtration chromatography and sedimentation-velocity analysis were used to examine the effect of BPTES on the phosphate-dependent oligomerization of KGA. This established that BPTES prevents the formation of large phosphate-induced oligomers and instead promotes the formation of a single oligomeric species with distinct physical properties. Sedimentation-equilibrium studies determined that the oligomer produced by BPTES is a stable tetramer. Taken together, the present work indicates that BPTES is a unique and potent inhibitor of rat KGA and elucidates a novel mechanism of inactivation.

Click Chemistry: Diverse Chemical Function from a Few Good Reactions.

Abstract: Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Abstract: The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.