A5065542161- Melanoma and MAPK Pathways
- Cytokine Signaling Pathways and Interactions
- Mathematical Biology Tumor Growth
- PI3K/AKT/mTOR signaling in cancer
- Synthesis and biological activity
- Cancer Mechanisms and Therapy
- Computational Drug Discovery Methods
- Bioinformatics and Genomic Networks
- Chronic Myeloid Leukemia Treatments
- RNA Interference and Gene Delivery
- Gene expression and cancer classification
- Monoclonal and Polyclonal Antibodies Research
- Nanoparticle-Based Drug Delivery
- Cell death mechanisms and regulation
- Dendrimers and Hyperbranched Polymers
- Gene Regulatory Network Analysis
- Multiple Myeloma Research and Treatments
- Receptor Mechanisms and Signaling
- Cell Adhesion Molecules Research
- Advanced Proteomics Techniques and Applications
- Mass Spectrometry Techniques and Applications
- Angiogenesis and VEGF in Cancer
- HER2/EGFR in Cancer Research
- Cancer Cells and Metastasis
- Statistical Methods in Clinical Trials
AstraZeneca (United States)
2014-2025
Takeda (United States)
2022-2023
Biogen (United States)
2021-2022
Homerton University Hospital
2017
Agriculture Victoria Services (Australia)
2017
Flinders Medical Centre
2017
Harvard University
2002-2010
Dana-Farber Cancer Institute
2010
University of Toronto
2010
Merrimack Pharmaceuticals (United States)
2008-2010
Abstract Mcl-1 is a member of the Bcl-2 family proteins that promotes cell survival by preventing induction apoptosis in many cancers. High expression causes tumorigenesis and resistance to anticancer therapies highlighting potential inhibitors as drugs. Here, we describe AZD5991, rationally designed macrocyclic molecule with high selectivity affinity for currently clinical development. Our studies demonstrate AZD5991 binds directly induces rapid cancer cells, most notably myeloma acute...
Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and therefore target interest for immunooncology. Nonselective HPK1 inhibitors may affect other components activation, blunting beneficial impact enhanced activity that results from inhibition itself. Here, we report discovery pyrazine carboxamide their optimization through structure-based drug design to afford highly selective inhibitor, compound 24 (AZ3246). This induces IL-2 secretion...
We compare several commonly used expression-based gene clustering algorithms using a figure of merit based on the mutual information between cluster membership and known attributes. By studying various publicly available expression data sets we conclude that enrichment clusters for biological function is, in general, highest at rather low numbers. As measure dissimilarity patterns two genes, no method outperforms Euclidean distance ratio-based measurements, or Pearson non-ratio-based...
Several years after sequencing the human genome and mouse genome, much remains to be discovered about functions of most genes. Computational prediction gene function promises help focus limited experimental resources on likely hypotheses. algorithms using diverse genomic data have been applied this task in model organisms; however, performance such approaches mammals has not yet evaluated. In study, a standardized collection functional was assembled; nine bioinformatics teams used set...
Evidence for specific protein–protein interactions is increasingly available from both small- and large-scale studies, can be viewed as a network. It has previously been noted that errors are frequent among error frequency depends on the method used. Despite knowledge of error-prone nature interaction evidence, edges (connections) in this network typically either present or absent. However, use probabilistic considers quantity quality supporting evidence should improve inference derived...
Abstract Dual Bcl-2/Bcl-x L inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design development of AZD0466, drug-dendrimer conjugate, where...
The RAS/MAPK pathway is a major driver of oncogenesis and dysregulated in approximately 30% human cancers, primarily by mutations the BRAF or RAS genes. extracellular-signal-regulated kinases (ERK1 ERK2) serve as central nodes within this pathway. feasibility targeting has been demonstrated clinical responses observed through use MEK inhibitors V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have utility overcoming acquired to RAF...
Abstract Background: Learning the function of genes is a major goal computational genomics. Methods for inferring gene have typically fallen into two categories: 'guilt-by-profiling', which exploits correlation between and other characteristics; 'guilt-by-association', transfers from one to another via biological relationships. Results: We developed strategy (' Funckenstein ') that performs guilt-by-profiling guilt-by-association combines results. Using benchmark set functional categories...
Abstract Purpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, had success the clinic, another member, Bcl-xL, also target and mechanism resistance. Therefore, we developed dual Bcl-2/Bcl-xL inhibitor that broadens therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design small-molecule Bcl-xL...
ABSTRACT In Saccharomyces cerevisiae , the ATF/CREB transcription factor Sko1 (Acr1) regulates expression of genes induced by osmotic stress under control high osmolarity glycerol (HOG) mitogen-activated protein kinase pathway. By combining chromatin immunoprecipitation and microarrays containing essentially all intergenic regions, we estimate that yeast cells contain approximately 40 target promoters in vivo; 20 were validated direct analysis individual loci. The consensus sequence is not...
The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and frequently dysregulated human cancers, primarily by mutations BRAF or RAS genes. clinical benefit of inhibitors this as single agents has only been realized BRAF-mutant melanoma, with limited effect single-agent KRAS-mutant tumors. Combined inhibition multiple nodes within pathway, such MEK1/2 ERK1/2, may be necessary to effectively suppress tumors achieve meaningful benefit. Here, we report...
Quantitative Systems Pharmacology (QSP) modeling is increasingly applied in the pharmaceutical industry to influence decision making across a wide range of stages from early discovery clinical development post-marketing activities. Development standards for how these models are constructed, assessed, and communicated active interest community regulators but complicated by variability structures intended uses underlying diverse expertise QSP modelers. With this mind, IQ Consortium conducted...
Chromatin immunoprecipitation combined with microarray technology (Chip2) allows genome-wide determination of protein-DNA binding sites. The current standard method for analyzing Chip2 data requires additional control experiments that are subject to systematic error. We developed methods assess significance using variance stabilization, learning error-model parameters without external experiments. was validated experimentally, shows greater sensitivity than the method, and incorporates...
Individual researchers are struggling to keep up with the accelerating emergence of high-throughput biological data, and extract information that relates their specific questions. Integration accumulated evidence should permit form fewer - more accurate hypotheses for further study through experimentation. Here a method previously used predict Gene Ontology (GO) terms Saccharomyces cerevisiae (Tian et al.: Combining guilt-by-association guilt-by-profiling gene function. Genome Biol 2008,...
Tandem mass spectrometry is commonly used to identify peptides (and thereby proteins) that are present in complex mixtures. Peptide identification from tandem spectra partially automated, but still requires human curation resolve "borderline" peptide-spectrum matches (PSMs). SILVER web-based software assists manual of spectra, using a recently developed intensity-based machine-learning approach scoring PSMs, Elias et al. In this method, large training set peptide, fragment, and...
Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) changes seen vivo and reduces predictive value of data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, Microformulator, which allows like PK profiles be applied cells cultured microtiter plates facilitates investigation impact biological responses. We demonstrate...
Abstract Summary: Computational gene function prediction can serve to focus experimental resources on high-priority tasks. FuncBase is a web resource for viewing quantitative machine learning-based annotations. Quantitative annotations of genes, including fungal and mammalian with Gene Ontology terms are accompanied by community feedback system. Evidence underlying shown. For example, custom Cytoscape viewer shows functional linkage graphs relevant the or interest. provides links external...
Abstract MM-111 is a novel bispecific antibody fusion protein which targets the ErbB2/ErbB3 oncogenic unit, blocking activation of phosphatidylinositol 3-kinase (PI3K) pro-survival pathway. The anti-ErbB2 arm binds with high affinity to ErbB2 receptor, localizes molecule over-expressing tumor cells and promotes binding anti-ErbB3 ErbB3 receptor. results in inhibition signaling by physiological ligand heregulin. treatment overexpressing cancer inhibits PI3K pathway sub-nanomolar potency,...
Abstract The induction of apoptosis in tumor cells represents a promising approach to the treatment cancer. In cells, B cell lymphoma 2 (Bcl-2) protein family promotes survival through upregulation anti-apoptotic Bcl-2 proteins, such as Bcl-2, Bcl-xL, Mcl-1 and Bcl-w. Clinical activity inhibitor venetoclax has validated targeting this class molecules, but additional value remains jointly with other members. AZD0466 is novel drug-dendrimer conjugate, where active moiety, AZD4320, chemically...