A5044566453- Cell death mechanisms and regulation
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Monoclonal and Polyclonal Antibodies Research
- Multiple Myeloma Research and Treatments
- Peptidase Inhibition and Analysis
- Protein Structure and Dynamics
- Glycosylation and Glycoproteins Research
- Chemical Synthesis and Analysis
- Advanced NMR Techniques and Applications
- Cytokine Signaling Pathways and Interactions
- Enzyme Structure and Function
- Synthesis and biological activity
- Lung Cancer Treatments and Mutations
- melanin and skin pigmentation
- NF-κB Signaling Pathways
- Cancer-related Molecular Pathways
- RNA and protein synthesis mechanisms
- Cancer, Hypoxia, and Metabolism
- Cell Adhesion Molecules Research
- Immune Response and Inflammation
- Microtubule and mitosis dynamics
- Cancer Mechanisms and Therapy
- NMR spectroscopy and applications
- Computational Drug Discovery Methods
PDL BioPharma (United States)
1996-2023
Genentech
1992-2015
South Texas Accelerated Research Therapeutics
2013
Tennessee Oncology
2013
Sarah Cannon
2013
National Institute of Occupational Health
2008
Molecular Oncology (United States)
2002-2004
University of Cincinnati
1999
Purdue University West Lafayette
1994
Scripps Research Institute
1992
The inhibitor of apoptosis (IAP) proteins are a family anti-apoptotic regulators found in viruses and metazoans. c-IAP1 c-IAP2 recruited to tumor necrosis factor receptor 1 (TNFR1)-associated complexes where they can regulate receptor-mediated signaling. Both have been implicated TNFalpha-stimulated NF-kappaB activation. However, individual gene knock-outs mice did not reveal changes TNF signaling pathways, the phenotype combined deficiency c-IAPs has yet be reported. Here we investigate...
The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy these settings is limited by thrombocytopenia caused BCL-XL inhibition. This prompted the generation of BCL-2-selective venetoclax (ABT-199/GDC-0199), which demonstrates robust cancers but spares platelets. Navitoclax also been to enhance docetaxel preclinical models solid tumors, use this combination neutropenia. We...
Abstract The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption high-affinity protein–protein interactions, therefore designing small molecules potent enough to inhibit in cells has proven extremely challenging. Here, we describe series indole-2-carboxylic acids,...
BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, cells are sensitive to antagonists that selectively target prosurvival such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or only (ABT-199/GDC-0199/venetoclax). Resistance these three drugs is mediated by expression MCL-1. However, given the selectivity profile venetoclax it unclear whether coexpression BCL-XL also affects antitumor responses in myeloma. In cell lines (n =...
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....
A series of compounds were designed and synthesized as antagonists cIAP1/2, ML-IAP, XIAP based on the N-terminus, AVPI, mature Smac. Compound 1 (GDC-0152) has best profile these compounds; it binds to BIR3 domain, BIR domain domains cIAP1 cIAP2 with K(i) values 28, 14, 17, 43 nM, respectively. These promote degradation cIAP1, induce activation caspase-3/7, lead decreased viability breast cancer cells without affecting normal mammary epithelial cells. inhibits tumor growth when dosed orally...
Receptor-interacting protein (RIP), a Ser/Thr kinase component of the tumor necrosis factor (TNF) receptor-1 signaling complex, mediates activation nuclear κB (NF-κB) pathway. RIP2 and RIP3 are related kinases that share extensive sequence homology with domain RIP. Unlike RIP, which has C-terminal death domain, RIP2, caspase recruitment possesses unique C terminus. binds RIP through this segment to inhibit RIP- TNF receptor-1-mediated NF-κB activation. We have identified homotypic...
Inhibitor of apoptosis (IAP) proteins are negative regulators cell death. IAP family members contain RING domains that impart E3 ubiquitin ligase activity. Binding endogenous or small-molecule antagonists to select baculovirus repeat (BIR) within cellular (cIAP) promotes autoubiquitination and proteasomal degradation so releases inhibition mediated by cIAP. Although the molecular details antagonist-BIR domain interactions well understood, it is not clear how this binding event influences...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTBackbone dynamics of the Bacillus subtilis glucose permease IIA domain determined from nitrogen-15 NMR relaxation measurementsMartin J. Stone, Wayne Fairbrother, Arthur G. Palmer, III, Jonathan Reizer, Milton H. Saier, Jr., and Peter E. WrightCite this: Biochemistry 1992, 31, 18, 4394–4406Publication Date (Print):May 12, 1992Publication History Published online1 May 2002Published inissue 12...
Peptides that inhibit binding of vascular endothelial growth factor (VEGF) to its receptors, KDR and Flt-1, have been produced using phage display. Libraries short disulfide-constrained peptides yielded three distinct classes bind the receptor-binding domain VEGF with micromolar affinities. The highest affinity peptide was also shown antagonize VEGF-induced proliferation primary human umbilical cells. a region known contain contact surface for Flt-1 functional determinants binding. This...