A5000020580- Cancer-related Molecular Pathways
- Mast cells and histamine
- Synthesis and Catalytic Reactions
- Immune cells in cancer
- Cancer Research and Treatments
- Fibroblast Growth Factor Research
- Cancer, Hypoxia, and Metabolism
- Cancer Mechanisms and Therapy
- Wnt/β-catenin signaling in development and cancer
- Cancer, Stress, Anesthesia, and Immune Response
- Advanced Breast Cancer Therapies
- Melanoma and MAPK Pathways
- Hippo pathway signaling and YAP/TAZ
- Colorectal Cancer Treatments and Studies
- Immune Cell Function and Interaction
- Adenosine and Purinergic Signaling
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- Cancer Immunotherapy and Biomarkers
- Enzyme function and inhibition
- Ubiquitin and proteasome pathways
- Mechanisms of cancer metastasis
- Estrogen and related hormone effects
- PI3K/AKT/mTOR signaling in cancer
- RNA modifications and cancer
AstraZeneca (United States)
2018-2024
Novartis (United States)
2007-2017
Foundation for Biomedical Research
2012-2014
Dana-Farber Cancer Institute
2001-2014
Novartis (Switzerland)
2012
Harvard University
2002-2007
McGill University
2000-2005
Montreal Children's Hospital
2005
Duke Medical Center
2004
Brigham and Women's Hospital
2003-2004
Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has intense interest developing agents suitable for modulating pathway vivo by targeting this enzyme pair. By utilizing a combination of structure-based design LipE-based structure efficiency relationships, core XAV939 was optimized into more stable, efficient, but less potent dihydropyran motif 7. This combined with elements screening hits 2, 19, 33 resulted highly potent, selective...
Accumulation of extracellular adenosine within the microenvironment is a strategy exploited by tumors to escape detection immune system. Adenosine signaling through 2A receptor (A2AR) on cells elicits range immunosuppressive effects which promote tumor growth and limit efficacy checkpoint inhibitors. Preclinical data with A2AR inhibitors have demonstrated regressions in mouse models rescuing T cell function; however, mechanism role other has not been fully elucidated.We report here...
A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis cancer cells dependent on for survival. We report the optimization series amidopyridines (from compound 2), focusing properties suitable achieving after intravenous administration. By increasing potency and human metabolic clearance, we identified 24, potent selective with predicted pharmacokinetic to deliver transient inhibition CDK9. Furthermore, solubility 24 was considered...
Agonist-mediated degradation of estrogen receptor α (ERα) has been associated with its transcriptional activity. However, the mechanism by which ERα is targeted for and whether there a direct functional link between stability ERα-mediated transactivation have not elucidated. Here we provide evidence that p160 coactivator, AIB1, uniquely mediates agonist-induced, but antagonist-induced, degradation. We show AIB1 recruitment only necessary also sufficient to promote Suppression levels leads...
Panobinostat (LBH589) is a highly potent deacetylase inhibitor that has demonstrated clinical efficacy in patients with advanced cutaneous T-cell lymphoma (CTCL). To gain better understanding of the compound activity this tumor type, we investigated cellular and molecular effects panobinostat using both vitro vivo models CTCL. All 4 tested CTCL cell lines exhibited very high sensitivity to panobinostat-induced growth inhibition. However, only 2 significant response cytotoxic panobinostat. In...
CITED1, a CBP/p300-binding nuclear protein that does not bind directly to DNA, is transcriptional coregulator. Here, we show evidence CITED1 functions as selective coactivator for estrogen-dependent transcription. When transfected, enhanced activation by the ligand-binding/AF2 domain of both estrogen receptor-α (ERα) and ERβ in an manner, but it affected activities other receptors only marginally. bound ERα manner through its transactivating domain, this binding activity was separable from...
The Wnt signaling pathway is critical to the regulation of key cellular processes. When deregulated, it has been shown play a crucial role in growth and progression multiple human cancers. identification small molecule modulators proven challenging, largely due relative paucity druggable nodes this pathway. Several recent publications have identified inhibitors pathway, tankyrase (TNKS) inhibition demonstrated antagonize via axin stabilization. Herein, we report early hit assessment series...
We report here the identification and characterization of a novel nuclear receptor coactivator, ERAP140.ERAP140 was isolated in screen for ER␣-interacting proteins using ER␣ ligand binding domain as probe.The ERAP140 protein shares no sequence has little structural homology with other cofactors.However, homologues have been identified mouse, Drosophila, Caenorhabditis elegans.The expression is cell tissue type specific most abundant brain, where its restricted to neurons.In addition...
Abstract Background The NCOA7 gene product is an estrogen receptor associated protein that highly similar to the human OXR1 product, which functions in oxidation resistance. OXR genes are conserved among all sequenced eukaryotes from yeast humans. In this study we examine if has resistance function demonstrated for OXR1. We also expression response oxidative stress and its subcellular localization cells, comparing these properties with those of Results find NCOA7, like can suppress mutator...
MELK kinase has been implicated in playing an important role tumorigenesis. Our previous studies suggested that is involved the regulation of cell cycle and its genetic depletion leads to growth inhibition a subset high MELK-expressing basal-like breast cancer lines. Herein we describe discovery optimization novel inhibitors 8a 8b recapitulate cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated knockdown models. We also discovered fluorine-induced hydrophobic...
RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase KRAS mutant tumors has established genetically engineered mouse models and tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective cellular potent inhibitors remain challenging identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as their preparation . WO 2014151616, 2014...
Abstract Background: BGB-3245 is a RAF dimer inhibitor with preclinical activity in MAPK-altered tumor models harboring BRAF V600 mutations, atypical mutations/fusions, and RAS mutations. This study investigating the safety, pharmacokinetics, preliminary antitumor of patients (pts) advanced or refractory solid tumors. Methods: Eligible pts were ≥18 yrs old ECOG 0-1 had tumors MAPK pathway alterations. Dose-escalation cohort-size decisions made using Modified Toxicity Probability Interval...
Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening a large panel of cancer cell lines, we have identified strong synergy between TNKS MEK inhibitors (MEKi) KRAS-mutant cells. Our study uncovers novel function the relief feedback loop induced by inhibition on FGFR2 signaling pathway. Moreover, dual leads to more robust apoptosis antitumor activity both vitro vivo than...
Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well attenuated hERG inhibition, were identified, suggesting that introduction molecular rigidity is viable strategy to enhance binding mitigate liability. Further SAR studies around 3-piperidin-3-ylindole moiety resulted in discovery compound 30, for which unique...
Tankyrases 1 and 2 are members of the poly(ADP-ribose) polymerase (PARP) family enzymes that modulate Wnt pathway signaling. While amide- lactam-based nicotinamide mimetics inhibit tankyrase activity, such as XAV939, well-known, herein we report discovery evaluation a novel isostere demonstrates selectivity over other PARP members. We demonstrate utilization lipophilic efficiency-based structure-efficiency relationships (SER) to rapidly drive this series. These efforts led series selective,...
Optimization of a series azabenzimidazoles identified from screening hit 2 and the information gained co-crystal structure azabenzimidazole-based lead 6 bound to CDK9 led discovery azaindoles as highly potent selective inhibitors. With goal discovering inhibitor administrated intravenously that would enable transient target engagement for treatment hematological malignancies, further optimization focusing on physicochemical pharmacokinetic properties 38 39. These compounds are inhibitors...
Arginase is a promising immuno-oncology target that can restore the innate immune response. However, it's highly polar active site often requires potent inhibitors to mimic amino acids, leading poor passive permeability and low oral exposure. Using structure-based drug design, we discovered novel proline-based arginase inhibitor (
Abstract Antitumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment, including recruitment of arginase (ARG) expressing myeloid cells that deplete l-arginine essential for optimal T-cell and natural killer cell function. Hence, ARG inhibition reverse immunosuppression enhancing antitumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, inhibitor payload (AZD0011-PL). demonstrate...
Abstract Cyclin-dependent kinase 9 (CDK9) regulates elongation of transcription through phosphorylation RNA polymerase II (pSer2-RNAPII), and its short-term inhibition downregulates genes with short-lived transcripts labile proteins. We developed a novel selective CDK9 inhibitor, AZD4573, nanomolar potency physicochemical properties suitable for IV administration short exposure. Initial transcriptomic proteomic analyses were performed on MCF7 breast cancer cells treated AZD4573 4h or 8h to...