University of California

Yale University

Buck Institute for Research on Aging

University of Texas System

Jonathan A Ellman

Ingrid Choong

Fanqing Frank Chen

Luke P Lee

Charles S Craik

Gang Logan Liu

Bradley J Backes

Irwin D Kuntz

Jennifer Harris

Lisa M Ellerby

A Geoffrey Skillman

Christina E Lee

Melissa J Leyva

Xiang Zhang

Robert A Newman

Fabrizio Micheli

Gary S Lynch

Cheng Sun

Robert G Bergman

Denton Wade Hoyer

Karen S Anderson

Anton Bennett

Xiaoning Bi

Victor A Levin

Diana C Roe

Raymond J Budde

Claudia Beato

Elias Lolis

Kai-Hang Su

Ellen K Kick

Qi-Huo Wei

Guangcheng Liu

Andrew W Patterson

Gary E Gallick

Hillary Peltier

Song Chen

Ya Ha

Caroline Chandra Tjin

Agostino Cianciulli

Elena Arceo Rebollo

Peter C Marsden

Tasir Haque

Haya Jamali

Gang L Liu

The present-disclosure relates to the discovery of novel 2-amino-dihydropteridinone compounds and analogues thereof, which are capable of inhibiting phosphatidylinositol phosphate kinases. In certain embodiments, the compounds of the present disclosure can be used to treat p53-null cancer in a subject. In other embodiments, the compounds of the present disclosure can be used to treat metabolic disorders in a subject, including but not limited to type 2 diabetes and/or obesity.

Small-molecule PI5P4K alpha/beta inhibitors and methods of treatment using same

The present invention provides compounds and methods for treating, ameliorating, and/or preventing a MKP-5 modulated disease. In certain embodiments, the MKP-5 modulated disease is a fibrotic disease.

Compounds and compositions for treating fibrosis

This invention provides novel caspase inhibitors useful for prophylaxis or treatment of a number of pathologies, including, for example, Huntington's disease. In certain embodiments the inhibitors include inhibitors of casepase-3 and/or casepase-6.

Caspase inhibitors and uses thereof

This invention pertains to the in vitro detection of proteases using a single peptide-conjugate nanocrescent surface enhanced Raman scattering (SERS) probes with at least nanomolar sensitivity. The probe enables detection of proteolytic activity in extremely small volume and at low concentration. In certain embodiments the probes comprise an indicator for the detection of an active protease, where the indicator comprises a nanocrescent attached to a peptide, where said peptide comprises a recognition site for the protease and a Raman tag attached to the peptide.

Detection of protease and protease activity using a single nanocrescent SERS probe

A nanoplasmonic resonator (NPR) comprising a metallic nanodisk with alternating shielding layer(s), having a tagged biomolecule conjugated or tethered to the surface of the nanoplasmonic resonator for highly sensitive measurement of enzymatic activity. NPRs enhance Raman signals in a highly reproducible manner, enabling fast detection of protease and enzyme activity, such as Prostate Specific Antigen (paPSA), in real-time, at picomolar sensitivity levels. Experiments on extracellular fluid (ECF) from paPSA-positive cells demonstrate specific detection in a complex bio-fluid background in real-time single-step detection in very small sample volumes.

Real-time, single-step bioassay using nanoplasmonic resonator with ultra-high sensitivity

The present invention provides novel tubulysin analogues, methods of making and methods of using such analogues and conjugates thereof. The compounds of the invention are highly potent cell-growth inhibitors have been developed that are smaller and considerably more stable than tubulysin D.

Tubulysin D analogues

Detection of protease and protease activity using a single nanoscrescent SERS probe

A method of preparing an olefin comprising: reacting a polyol in the presence of a carboxylic acid, such that an olefin is produced by the deoxygenation of the polyol. The reacting step can comprise (a) providing a composition comprising the polyol, (b) heating the composition, and (c) introducing the carboxylic acid to the composition wherein the introducing step occurs prior to, at the same time as, or subsequent to the heating step. In one embodiment, the polyol is glycerol, the carboxylic acid is formic acid, and the olefin is allyl alcohol, which is produced at a yield of about 80% or greater.

Method of converting a polyol to an olefin

A method is presented for the preparation and use of fluorogenic peptide substrates that allows for the configuration of general substrate libraries to rapidly identify the primary and extended specificity of enzymes, such as proteases. The substrates contain a fluorogenic-leaving group, such as 7-amino-4-carbamoylmethyl-coumarin (ACC). Substrates incorporating the ACC leaving group show comparable kinetic profiles as those with the traditionally used 7-amino-4-methyl-coumarin (AMC) leaving group. The bifunctional nature of ACC allows for the efficient production of single substrates and substrate libraries using solid-phase synthesis techniques.

Fluorogenic materials and uses thereof

The present invention relates to () non-peptide aspartyl protease inhibitors; (ii) methods for modulating the processing of an amyloid precursor protein (APP); (iii) methods for modulating the processing of a tau protein (&#x3c4;-protein); and (iv) methods for treating neurodegenerative diseases. For instance, in one embodiment, the present invention provides a method for modulating the processing of an amyloid precursor protein (APP), the method comprising contacting a composition containing the APP with an aspartyl protease inhibitor having the formula: wherein: RRand Rare members independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl, substituted aryloxyalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycles, substituted heterocycles, heterocyclicalkyl and substituted heterocyclicalkyl; and Rand Rare independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl and substituted aryloxyalkyl; or Rand Rand the carbons to which they are bound join to form an optionally substituted carbocyclic or heterocyclic fused ring system having a total of 9- or 10-ring atoms within the fused ring system.

Methods for treating neurodegenerative disorders using aspartyl protease inhibitors

A library of candidate target binding fragments (CTBF's) each CTBF being a small organic molecule and having a linkable functional group (LFG) or blocked form thereof (BLFG), wherein the LFG or BLFG contains a linking group (LG), the LG being a disulfide group.

Pharmacophore recombination for the identification of small molecule drug lead compounds

A method is presented for the preparation and use of fluorogenic peptide substrates that allows for the configuration of general substrate libraries to rapidly identify the primary and extended specificity of enzymes, such as proteases. The substrates contain a fluorogenic-leaving group, such as 7-amino-4-carbamoylmethyl-coumarin (ACC). Substrates incorporating the ACC leaving group show comparable kinetic profiles as those with the traditionally used 7-amino-4-methyl-coumarin (AMC) leaving group. The bifunctional nature of ACC allows for the efficient production of single substrates and substrate libraries using solid-phase synthesis techniques. The approximately 3-fold increased quantum yield of ACC over AMC permits reduction in enzyme and substrate concentrations. As a consequence, a greater number of substrates can be tolerated in a single assay, thus enabling an increase in the diversity space of the library. Soluble positional protease substrate libraries of 137,180 and 6,859 members, possessing amino acid diversity at the P4-P3-P2-P1 and P4-P3-P2 positions, respectively, were constructed. Employing this screening method the substrate specificities of a diverse array of proteases were profiled, including the serine proteases thrombin, plasmin, factor Xa, uPA, tPA, granzyme B, trypsin, chymotrypsin, human neutrophil elastase, and the cysteine proteases papain and cruzain. The resulting profiles create a pharmacophoric portrayal of the proteases allowing for the design of selective substrates and potent inhibitors.

Profiling of protease specificity using combinatorial fluorogenic substrate libraries

The present invention is directed to novel methods for identifying small molecule ligands that are capable of binding with high affinity to a biological target molecule of interest. High affinity binding ligands identified by the described methods find use, for example, as small molecule lead compounds that may they themselves be, or may give rise to, novel therapeutic drugs. More specifically, the subject invention is directed to methods for identifying a ligand that binds to a target biological molecule of interest, wherein a population of small organic compounds are selected and then &ldquo;pre-screened&rdquo; to identify those that are capable of binding to the molecular target. The small organic compounds that are identified during the pre-screening as being capable of binding to the target (or structurally related analogs thereof) are then coupled in various combinations with a linker element to provide a library of potential ligands for binding to the target molecule that is then screened to identify ligands having very high binding affinities for the molecular target. Ligands obtained by this method and methods for using those ligands for inhibiting the interaction between two biological molecules are also provided.

Method for identifying a drug lead compound that inhibits binding of target bioogical molecules (TBM) by contacting TBM with members of a library of candidate cross-linked target binding fragments (CXBF), each CXBF having at least two candidate target bindig fragments (CTBF), which are inhibitors of binding, linked to a cross-linker, and selecting CXBF that inhibit the binding of the TBM to a greater extent than either of the individual CTBF linked to said cross-linker, wherein the library of CXBF is produced by: (a) screening a population of CTBF capable of being chemically cross-linked by a cross-linker to identify a subpopulation of the CTBF that inhibit binding of the TBM; and (b) chemically cross-linking members of the subpopulation of CTBF or structurally related analogs thereof with a cross-linker to provide a library of CXBF, wherein at least one linking group comprises an oxime ether linking group.

Growing community of inventors

Oakland, CA, United States of America

Jonathan A Ellman