A5035637686- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Cell Adhesion Molecules Research
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Advanced Proteomics Techniques and Applications
- Alzheimer's disease research and treatments
- Mass Spectrometry Techniques and Applications
- Tryptophan and brain disorders
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- Computational Drug Discovery Methods
- Protein purification and stability
- Cancer, Hypoxia, and Metabolism
- Parkinson's Disease Mechanisms and Treatments
- Epigenetics and DNA Methylation
- Analytical Chemistry and Chromatography
- Biochemical and Molecular Research
- Genomics, phytochemicals, and oxidative stress
- Sirtuins and Resveratrol in Medicine
- Melanoma and MAPK Pathways
- Pharmacological Receptor Mechanisms and Effects
- Cholinesterase and Neurodegenerative Diseases
- Plant Gene Expression Analysis
Roche (United States)
2023
Gilead Sciences (United States)
2022
Genentech
2011-2015
WuXi AppTec (China)
2015
Toxicologie, Pharmacologie et Signalisation Cellulaire
2014
Amgen (United States)
2007-2013
Biochemical Society
2010
Brigham and Women's Hospital
2002-2009
Harvard University
2003-2009
A human antibody inhibits BACE1 activity and Aβ peptide production in cultured neurons the central nervous system of mouse monkey.
Antibody-drug conjugates (ADC) are designed to selectively bind tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable through judicious design of linker has been an early technological milestone. Here, we examine effect protease-cleavable valine-citrulline [VC(S)] on ADC efficacy. The VC(S) was be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression B expression CRISPR-Cas9 gene deletion or shRNA knockdown had no...
THIOMAB antibody technology utilizes cysteine residues engineered onto an to allow for site-specific conjugation. The has enabled the exploration of different attachment sites on in combination with small molecules, peptides, or proteins yield conjugates unique properties. As reported previously ( Shen , B. Q. et al. 2012 ) Nat. Biotechnol. 30 184 - 189 ; Pillow T. H. 2017 Chem. Sci. 8 366 370 ), specific location site conjugation can impact stability linkage both thio-succinimide and...
The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate that activated by the coagonists glycine glutamate. NMDARs are critical to synaptic signaling plasticity, their dysfunction has been implicated in number of neurological disorders, including schizophrenia, depression, Alzheimer's disease. Herein we describe discovery potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from high-throughput screening hit. Using...
Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is linked to Parkinson's disease (PD) and memory selectively expressed in neurons at high levels. Its expression pattern suggests a function distinct from that of its widely homolog UCH-L3. We report here that, contrast UCH-L3, UCH-L1 exists membrane-associated form (UCH-L1(M)) addition the commonly studied soluble form. farnesylation promotes association with cellular membranes, including endoplasmic reticulum. The amount UCH-L1(M) transfected...
Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that involved in several biological processes and plays central role the ubiquitin-mediated degradation misfolded proteins. VCP an ubiquitously expressed, highly abundant has been found overexpressed many tumor types, sometimes associated with poor prognosis. In this respect, recently received great deal attention potential new target for cancer therapy. paper, discovery structure-activity relationships...
Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer binding mode specific design parameters optimize for CNS druglike molecules, came focus on di(pyridin-2-yl)amines because their combination desirable potency good brain penetration following...
Mutations in the genetic sequence of leucine-rich repeat kinase 2 (LRRK2) have been linked to increased LRRK2 activity and risk for development Parkinson's disease (PD). Potent selective small molecules capable inhibiting will be important tools establishing a link between PD. In absence domain crystal structures, homology model was developed that provided robust guidance hit-to-lead optimization molecule inhibitors. Through combination molecular modeling, analysis, matched pair (MMP) cliff...
Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite progress, improvements ADC index are desired. Peptide-based linkers that cleaved lysosomal proteases shown sufficient stability serum effective payload-release targeted cells. If linker can be preferentially hydrolyzed tumor-specific proteases, safety margin may improve. However, use of peptide-based limits our ability to...
Previous investigations on antibody-drug conjugate (ADC) stability have focused drug release by linker-deconjugation due to the relatively stable payloads such as maytansines. Recent development of ADCs has been exploring technologies produce homogeneous and new classes expand mechanisms action delivered drugs. Certain ADC could undergo metabolism in circulation while attached antibodies thus affect stability, pharmacokinetics, efficacy toxicity profiles. Herein, we investigate payload...
Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following injury and in chronic neurodegenerative disease. Consequently, there considerable interest the identification DLK inhibitors with profile compatible development for these indications. Herein, we use structure-based drug design combined focus on CNS drug-like properties generate compounds superior selectivity metabolic stability as compared previously...
High throughput protein-ligand interaction screening assays employing mass spectrometric detection are widely used in early stage drug discovery. Mass spectrometry-based approaches employ a target protein added to pool of small-molecule compounds, and binding is assessed by measuring ligands denatured from the complexes. Direct analysis interactions using native spectrometry has been demonstrated but not due limit on size, requirement volatile buffers, necessity for specialized...
Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment a number indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe shape-based scaffold hopping approach convert pyrimidine 1 pyrazole core improved physicochemical properties. We also present the first...
Significance While electrospray ionization–mass spectrometry (ESI-MS) provides higher resolution for larger proteins, the conventional liquid chromatography (LC)-MS method suffers from low throughput. Our described RapidFire-MS workflow demonstrated unprecedented screening throughput as fast 15 s/sample, a 10-fold improvement over LC-MS approaches. The enabled selection of clones with highest purity bispecific antibody production intact masses accurate 7 ppm baseline at glycoform level in...
Abstract Prolonged inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a strategy for targeting cancer metabolism. Many NAMPT inhibitors undergo NAMPT‐catalyzed phosphoribosylation (pRib), property often correlated with their cellular potency. To understand this phenomenon and facilitate drug design, we analyzed potent cellularly active inhibitor (GNE‐617). A crystal structure pRib‐GNE‐617 in complex protein revealed relaxed binding mode. Consistently, the adduct formation...