A5041949186- Cancer-related Molecular Pathways
- Synthesis and Catalytic Reactions
- Mast cells and histamine
- Immune cells in cancer
- Cancer Research and Treatments
- Cancer, Stress, Anesthesia, and Immune Response
- Cancer, Hypoxia, and Metabolism
- Cancer Mechanisms and Therapy
- Immune Cell Function and Interaction
- Advanced Breast Cancer Therapies
- RNA modifications and cancer
- Chronic Lymphocytic Leukemia Research
- PI3K/AKT/mTOR signaling in cancer
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Lymphoma Diagnosis and Treatment
- Cancer Immunotherapy and Biomarkers
- PARP inhibition in cancer therapy
- T-cell and B-cell Immunology
- Inflammatory mediators and NSAID effects
- Immunotherapy and Immune Responses
- Liver physiology and pathology
- Chronic Myeloid Leukemia Treatments
- Lung Cancer Treatments and Mutations
- Cancer therapeutics and mechanisms
AstraZeneca (United States)
2015-2025
Kala Pharmaceuticals (United States)
2024
AstraZeneca (Brazil)
2020
Brown University
2008
Rhode Island Hospital
2008
Moores Cancer Center
2007
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...
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...
PARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased subsequent immune activation can prime an anti-tumor response, we studied the impact olaparib ± checkpoint blockade (ICB) on activity microenvironment. Concurrent combination olaparib, at clinically relevant exposures, ICB gave durable deeper Brca1m BR5 model vs. monotherapies. Olaparib treatment modulated microenvironment, including...
Abstract Cyclin-dependent kinases (CDKs) are an attractive class of cancer targets due to their role in cell-cycle regulation. CDK2 is a Ser/Thr kinase activated via interaction with its cyclin partners CCNE and CCNA, driving G1/S progression the cell cycle. inhibition has potential address multiple resistance mechanisms CDK4/6 inhibitors breast cancer. In addition, CCNE1 frequently amplified over-expressed cancers including ovarian, pre-clinical data linking sensitivity high CCNE1....
Inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition PPAT isozymes from several species, with most potent enzymes Gram-positive species. Mode-of-inhibition studies Streptococcus pneumoniae and Staphylococcus aureus demonstrated representatives this series to be reversible inhibitors competitive phosphopantetheine uncompetitive ATP, binding...
Hematopoietic Progenitor Kinase 1 (HPK1) is a negative regulator of T-cell signaling. Inhibition HPK1 with small molecules has been shown to reinvigorate the immune system toward fighting tumours in...
The current CLSI and EUCAST clinical susceptible breakpoint for 600 mg q12h dosing of ceftaroline (active metabolite fosamil) Staphylococcus aureus is ≤1 mg/L. Efficacy data S. infections with MIC ≥2 mg/L are limited. This study was designed to generate in-depth pharmacokinetic/pharmacodynamics (PK/PD) understanding isolates inhibited by ≥ 2 using an in vitro hollow-fibre infection model (HFIM). PK/PD target investigated against 12 diverse characterized MRSA MICs or 4 q8h 24 h. These carried...
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 2 (CDK2) is a Ser/Thr kinase activated via interaction with its cyclin partners CCNE and CCNA, driving G1/S progression of the cell cycle. CDK2 inhibition has potential to address multiple resistance mechanisms CDK4/6 inhibitors in breast cancer. In addition, CCNE1 frequently amplified over-expressed cancers including ovarian, uterine, breast, gastric others, pre-clinical data linking sensitivity high CCNE1. The inhibitor field historically suffered from...
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...
Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent, and highly MET receptor TK inhibitor. This series of studies aimed to develop a pharmacokinetic-pharmacodynamic (PK/PD) model link inhibition phosphorylation (pMET) by savolitinib with anti-tumour activity.Cell line-derived xenograft (CDX) experiments using human lung cancer (EBC-1) gastric (MKN-45) cells were conducted in athymic nude mice variety doses schedules savolitinib. Tumour pMET changes growth calculated after 28 days....
Abstract Cyclin-dependent kinase 9 (CDK9) is a serine/threonine that regulates elongation of transcription through phosphorylation RNA polymerase II at serine 2 (p-Ser2-RNAPII). Transient inhibition CDK9 results in reduced protein levels for genes have short half-lives transcripts and proteins, thus presenting potential therapeutic opportunity tumors dependent upon oncogenes fitting such criteria. One example Mcl-1, an anti-apoptotic plays key role cancer cell survival. A potent selective...
Abstract Cyclin-dependent kinase 9 (CDK9) regulates transcription elongation through phosphorylation of RNA polymerase II at serine 2 (pSer2-RNAPII), and its short-term inhibition downregulates genes with short-lived transcripts labile proteins, thus providing a mechanism to inhibit key survival proteins like Mcl1 Myc. We developed selective CDK9 inhibitor, AZD4573, that exhibits anticancer activity across diverse set hematologic cell lines is being evaluated in patients malignancies....
7031 Background: The molecular pathogenesis of the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia has been strongly linked to an activating mutation JAK2 (Janus Associated Kinase 2). A G-T transversion event in exon 14 that translates into a substitution phenylalanine for valine at amino acid residue 617 leads constitutive activation V617F majority these MPD cases. Methods: In order address this unmet clinical need...
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<div>Abstract<p>Anti-tumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment including recruitment of arginase (ARG) expressing myeloid cells which deplete L-arginine essential for optimal T cell and natural killer function. Hence, ARG inhibition reverse immunosuppression enhancing anti-tumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, inhibitor payload (AZD0011-PL)....