A5078585814- Antibiotic Resistance in Bacteria
- Microbial Natural Products and Biosynthesis
- PI3K/AKT/mTOR signaling in cancer
- Peptidase Inhibition and Analysis
- Enzyme function and inhibition
- Hippo pathway signaling and YAP/TAZ
- Protein Kinase Regulation and GTPase Signaling
- Chemical Synthesis and Analysis
- Bacterial Genetics and Biotechnology
- Cancer therapeutics and mechanisms
- Marine Sponges and Natural Products
- Cell death mechanisms and regulation
- Ubiquitin and proteasome pathways
- Click Chemistry and Applications
- Drug Transport and Resistance Mechanisms
- Signaling Pathways in Disease
- Monoclonal and Polyclonal Antibodies Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer Treatment and Pharmacology
- Quinazolinone synthesis and applications
- Cancer-related gene regulation
- Bacteriophages and microbial interactions
- Synthetic Organic Chemistry Methods
- 14-3-3 protein interactions
- Synthesis of Organic Compounds
Genentech
2010-2014
PDL BioPharma (United States)
2009
Stanford University
1998-2003
Arizona State University
1998
Kyoto University
1998
Cancer Research Institute
1998
A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening structure-based design. This compound is substantially more against BCL-XL-dependent cell lines relative to our recently reported WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused mechanism-based reversible thrombocytopenia in mice inhibited H146 small lung cancer xenograft tumor growth vivo following multiple doses....
The LAP (leucine-rich repeatand PDZ-containing) family of proteins play a role in maintaining epithelial and neuronal cell size, mutation these can have oncogenic consequences. protein Erbin has been implicated previously number cellular activities by virtue its PDZ domain-dependent association with the C termini both ERB-B2 p120-catenins. present work describes NMR structure complex high affinity peptide ligand includes comprehensive energetic analysis domain side chains responsible for...
Erbin is a recently described member of the LAP (leucine-rich repeat and PDZ domain) protein family. We used C-terminally displayed phage peptide library to identify optimal ligands for domain. Phage-selected peptides were type 1 that bound with high affinity specificity domain in vitro. These most closely resembled C-terminal domain-binding motifs three p120-related catenins: δ-catenin, ARVCF, p0071 (DSWV-COOH). Analysis interactions synthetic matching C termini ARVCF or δ-catenin also...
The inhibitor of apoptosis (IAP) proteins are critical regulators cancer cell survival, which makes them attractive targets for therapeutic intervention in cancers. Herein, we describe the structure-based design IAP antagonists with high affinities and selectivity (>2000-fold) c-IAP1 over XIAP their functional characterization as activators tumor cells. Although capable inducing death preventing clonogenic c-IAP-selective significantly less potent promoting when compared to pan-selective...
Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds developed into potent, selective CDK8 inhibitors. When cocrystallized and cyclin C, these exhibit an unusual binding mode, making single hydrogen bond the hinge residue A100, second K252, key cation-π interaction R356. Structure-based drug design resulted in tool 13 32, are highly kinase selective, permeable free fraction >2% no measurable efflux. Despite...
There is a critical need for new antibacterial strategies to counter the growing problem of antibiotic resistance. In Gram-negative bacteria, outer membrane (OM) provides protective barrier against antibiotics and other environmental insults. The leaflet primarily composed lipopolysaccharide (LPS). Outer biogenesis presents many potentially compelling drug targets as this pathway absent in higher eukaryotes. Most proteins involved LPS biosynthesis transport are essential; however, few...
The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities protein kinase C (PKC) isozymes, compete phorbol ester binding site on PKC, and stimulate in vitro vivo . Unlike esters, they first-stage tumor promoters. design, computer modeling, NMR solution structure, PKC binding, functional assays class synthetic bryostatin...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTSynthesis of the First Members a New Class Biologically Active Bryostatin AnaloguesPaul A. Wender, Jef De Brabander, Patrick G. Harran, Juan-Miguel Jimenez, Michael F. T. Koehler, Blaise Lippa, Cheol-Min Park, and Makoto ShiozakiView Author Information Department Chemistry, Stanford University Stanford, California 94305-5080 Cite this: J. Am. Chem. Soc. 1998, 120, 18, 4534–4535Publication Date (Web):April 23, 1998Publication History Received7...
ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-xL Bcl-2. This class putative anticancer agents invariantly contains an acylsulfonamide core. We have designed synthesized a series novel quinazoline-based Bcl-2 that contain heterocyclic alternative to acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines presence 10% serum. comprises first successful demonstration quinazoline sulfonamide...
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels selectivity for JAK1 over JAK2 to imidazopyrrolopyridine series inhibitors. X-ray structures analogue in complex with both and revealed differential ligand/protein interactions between two isoforms offered an explanation observed selectivity. Analysis historical data from related molecules was used develop set physicochemical compound design parameters impart desirable...
Using Sorafenib as a starting point, series of potent and selective inhibitors CDK8 was developed. When cocrystallized with cyclin C, these compounds exhibit Type-II (DMG-out) binding mode.
The effort to modulate challenging protein targets has stimulated interest in ligands that are larger and more complex than typical small-molecule drugs. While combinatorial techniques such as mRNA display routinely produce high-affinity macrocyclic peptides against classically undruggable targets, poor membrane permeability limited their use toward primarily extracellular targets. Understanding the passive of would, principle, improve our ability design libraries whose leads can be readily...
Herein we report the discovery of C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent orally bioavailable JAK1 inhibitors with selectivity over JAK2. The inhibitor 4 exhibited not only improved potency relative unsubstituted compound 3 but also notable vs JAK2 (20-fold >33-fold in biochemical cell-based assays, respectively). Features X-ray structures complex both are delineated. Efforts improve vitro vivo ADME properties while maintaining described,...
Pseudomonas aeruginosa causes life-threatening infections that are associated with antibiotic failure. Previously, we identified the G2637, an analog of arylomycin, targeting bacterial type I signal peptidase, which has moderate potency against P. aeruginosa. We hypothesized antibody-antibiotic conjugate (AAC) could increase its activity by colocalizing bacteria high local concentrations G2637 in intracellular environment phagocytes. Using a novel technology screening for hybridomas...
Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization advanced lead 1 culminated discovery clinical development candidate 8h, GDC-0349, a potent selective ATP-competitive inhibitor mTOR. GDC-0349 demonstrates modulation dose-dependent efficacy mouse xenograft cancer models.
Because of the promise BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest additional selective antiapoptotic proteins has grown. Beginning with a series selective, potent BCL-XL containing an undesirable hydrazone functionality, silico design X-ray crystallography were utilized to develop alternative scaffolds that retained selectivity potency starting compounds.
The dramatic increase in the prevalence of multi-drug resistant Gram-negative bacterial infections and simultaneous lack new classes antibiotics is projected to result approximately 10 million deaths per year by 2050. We report on efforts target ATP-binding cassette (ABC) transporter MsbA, an essential inner membrane protein that transports lipopolysaccharide from leaflet periplasmic face membrane. demonstrate improvement a high throughput screening hit into compounds with on-target single...
The preclinical work leading to the discovery of PF-07321332 (nirmatrelvir) is described in Featured Article summarized this Viewpoint. This resulted an Emergency Use Authorization (EUA) for Paxlovid within two years project's start. In addition medicinal chemistry approach taken, authors describe how they achieved remarkable speed.
Selective inhibitors of mammalian target rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with K(i) < 10 nM for the mTOR >500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation substrate proteins antiproliferative activity in cell lines constitutively active PI3K pathway. Two exhibiting suitable mouse PK...