A5049753385- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- PARP inhibition in cancer therapy
- Immunotherapy and Immune Responses
- Cancer therapeutics and mechanisms
- Iron Metabolism and Disorders
- Angiogenesis and VEGF in Cancer
- HER2/EGFR in Cancer Research
- Protein Degradation and Inhibitors
- Cancer Immunotherapy and Biomarkers
- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- DNA Repair Mechanisms
- Signaling Pathways in Disease
- Chemokine receptors and signaling
- Neuroblastoma Research and Treatments
- Lung Cancer Treatments and Mutations
- Microtubule and mitosis dynamics
- Cancer Treatment and Pharmacology
- Hemoglobinopathies and Related Disorders
- Hepatocellular Carcinoma Treatment and Prognosis
- Advanced Breast Cancer Therapies
- Medical Imaging Techniques and Applications
- Cancer, Lipids, and Metabolism
- Renal cell carcinoma treatment
AbbVie (United States)
2017-2023
Abbott (United States)
2005-2012
Institute of Cancer Research
2010
Abbott Fund
2003-2009
University of the Witwatersrand
1987-1989
ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that potent of members the vascular endothelial growth factor (VEGF) and platelet-derived (PDGF) families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 micromol/L) against unrelated RTKs, soluble kinases, or serine/threonine kinases. The inhibition profile evident in cellular assays RTK phosphorylation (IC50 2, 4, 7 nmol/L for PDGFR-beta, KDR, CSF-1R, respectively) VEGF-stimulated proliferation 0.2...
ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy xenograft models representing various human tumors having different responses to TMZ.ABT-888+TMZ efficacy implanted subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression polymer, O(6)-methylguanine methyltransferase (MGMT).Varying...
Nontypeable Haemophilus influenzae (NTHi) is a major cause of opportunistic respiratory tract infections, including otitis media and bronchitis. The persistence NTHi in vivo thought to involve bacterial biofilm community. Therefore, there need for further definition factors contributing formation by NTHi. Like other bacteria inhabiting host mucosal surfaces, has on its surface diverse array lipooligosaccharides (LOS) that influence host-bacterial interactions. In this study, we show LOS...
We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well single-digit nanomolar cellular potency. These efforts led to the identification (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed against PARP-1 K(i) 1 nM an EC(50) in whole cell assay. In addition, is orally bioavailable across...
7-Aminopyrazolo[1,5- a]pyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure-activity relationships the pyrazolo[1,5- nucleus led to a series 6-(4- N, N'-diphenyl)ureas that potently inhibited panel vascular endothelial growth factor (VEGFR) and platelet-derived (PDGFR) kinases. Several these compounds, such as 34a, are potent insert domain-containing (KDR) both enzymatically (<10 nM) cellularly nM). In addition, compound 34a possesses favorable...
This laboratory and others have shown that agents inhibit the in vitro catalytic activity of methionine aminopeptidase-2 (MetAP2) are effective blocking angiogenesis tumor growth preclinical models. However, these prototype MetAP2 inhibitors clearly not optimized for therapeutic use clinic. We discovered an orally active class inhibitors, anthranilic acid sulfonamides exemplified by A-800141, which is highly specific MetAP2. bioavailable inhibitor exhibits antiangiogenesis effect a broad...
Type 1 IFNs stimulate secretion of IP-10 (CXCL10) which is a critical chemokine to recruit effector T cells the tumor microenvironment and knockout mice exhibit phenotype with compromised cell generation trafficking. also induce MHC class upregulation on can enhance anti-tumor CD8 response in microenvironment. Although type show great promise potentiating immune response, systemic delivery associated toxicity thereby limiting clinical application. In this study, we fused targeting antibodies...
Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a associated antigen hold great promise in the clinic. However, ability safely and potently target CD3 on CTL toward antigens (TAA) expressed remains challenge of both technology biology. Herein we describe use Half DVD-Ig format can cells. Notably, molecules are monovalent for each specificity demonstrated reduced non-specific activation conditional upon binding TAA compared intact tetravalent bivalent...
CD3 bispecific T-cell engagers (TCE), comprised of a tumor-targeting domain linked to binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected cell-mediated killing tumor cells. Although the majority molecules in clinical development incorporate antibody-based domains, many tumor-associated antigens derive from intracellular proteins are not accessible targeting via antibody. Intracellular processed into short peptide fragments...
Abstract A study was done to find out whether apotransferrin receptors are involved in the release of iron from reticuloendothelial cells. To this end, human macrophages which had been obtained by culturing blood monocytes for 7 days were incubated with either diferric or at physiological pH 7.4 an acidic (6.0). While specific transferrin (K b 1.3 × 10 −8 M) demonstrated 7.4, no found. In contrast, both d 2.1 and 2.8 −9 found 6.0. The finding binding fits current understanding uptake cells,...
<div>Abstract<p>CD3 bispecific T cell engagers (TCE), comprised of a tumor targeting domain linked to CD3 binding domain, function by bridging target-positive tumors and CD3-expressing effector cells enabling redirected cell-mediated killing cells. Although the majority molecules in clinical development incorporate tumor-targeting antibody-based domains, many tumor-associated antigens derive from intracellular proteins are not accessible via antibody. Intracellular processed into...
<p>A prostate tumor cell line (PC3M-A2/beta 2M) was inoculated subcutaneously in the right flank of CD34-humanized NSG mice. Mice were treated intravenously at indicated time points with either vehicle or an ABBV-184 precursor molecule, and size monitored. Tumors experienced transient regression growth inhibition prior to harvest for analysis tumor-infiltrating immune cells.</p>
<p>A prostate tumor cell line (PC3M-A2/beta 2M) was inoculated subcutaneously in the right flank of CD34-humanized NSG mice. Mice were treated intravenously at indicated time points with either vehicle or an ABBV-184 precursor molecule, and size monitored. Tumors experienced transient regression growth inhibition prior to harvest for analysis tumor-infiltrating immune cells.</p>
Abstract A study was done to evaluate the effect of ferrous and ferric chelators on interaction between transferrin‐iron cultured human blood monocytes. This has been previously shown involve a specific receptor vesicle protonation. Transferrin‐iron uptake significantly inhibited by hydrophobic chelator 2,2′ bipyridine, inhibition not be consequence mobilisation intracellular iron chelator. Chase experiments prolonged incubation studies suggested that prevented released from transferrin...
Certain metabolic pathways of iron were studied in macrophages (cultured human monocytes) obtained from normal and hemochromatotic subjects. The relative abilities the hydrophobic ferrous chelator 2,2' bipyridine hydrophilic ferric chelators desferrioxamine (DFO) diethylenetriaminepenta-acetic acid (DTPA) to release which had previously been loaded with diferric transferrin tested but there no differences between two groups. affinity for was next studied. Although hemochromatic a somewhat...
Abstract The Aurora kinases are a family of serine/threonine that mediate essential functions in cell division. A depletion results accumulation cells the G2/M phase and apoptosis. Inhibition B/C abnormal division, polyploidy, resulting apoptosis, therefore, present an attractive target for chemotherapy. Cells treated with aurora inhibitors enter mitosis normal kinetics but fail to undergo cytokinesis due mitotic spindle checkpoint disruption. ABT-348 is novel adenosine triphosphate...
Abstract PARP's role in DNA damage recognition/repair makes PARP inhibition an attractive cancer therapeutic target. Veliparib (ABT-888) is a potent inhibitor with excellent oral bioavailability that readily crosses the blood-brain barrier and currently Phase 2 clinical trials. has shown significant ability to potentiate multiple damaging agents (cisplatin, carboplatin, cyclophosphamide, irinotecan, radiation temozolomide) spectrum of tumors from histological types. In studies using...
Abstract Type 1 IFNs stimulates secretion of IP-10 (CXCL10) which is a critical chemokine to recruit effector T cells the tumor microenvironment and knockout mice exhibit phenotype with compromised cell generation trafficking. also induces MHC class upregulation on can enhance anti-tumor CD8 response in microenvironment. Although type show great promise potentiating immune response, systemic delivery associated toxicity thereby limiting clinical application. In this study, we fused targeting...