A5013730565- PI3K/AKT/mTOR signaling in cancer
- Advanced Breast Cancer Therapies
- PARP inhibition in cancer therapy
- Melanoma and MAPK Pathways
- Cancer Genomics and Diagnostics
- Protein Kinase Regulation and GTPase Signaling
- Toxin Mechanisms and Immunotoxins
- Phytochemicals and Medicinal Plants
- FOXO transcription factor regulation
- Lung Cancer Treatments and Mutations
- Synthesis and biological activity
- Cancer Treatment and Pharmacology
- Chronic Lymphocytic Leukemia Research
- Biochemical and Molecular Research
- Cancer Diagnosis and Treatment
- Cancer-related Molecular Pathways
- Prostate Cancer Treatment and Research
- Cancer Mechanisms and Therapy
- Estrogen and related hormone effects
- Ovarian cancer diagnosis and treatment
- Peroxisome Proliferator-Activated Receptors
- CRISPR and Genetic Engineering
- Cell death mechanisms and regulation
- Lung Cancer Research Studies
- Neuroendocrine Tumor Research Advances
AstraZeneca (United Kingdom)
2016-2025
University of Bradford
2018
Cancer Research UK
2017
Levine Cancer Institute
2013
Novartis (Switzerland)
2013
AstraZeneca (Switzerland)
2013
The University of Texas MD Anderson Cancer Center
2013
Novartis Institutes for BioMedical Research
2013
Babraham Institute
2013
University of British Columbia
2012
The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, survival, autophagy. Allosteric inhibitors mTORC1, such as rapamycin, have been extensively used to study tumor proliferation, autophagy but shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor mTOR activity, with an IC50 0.8 nmol/L. AZD8055 showed excellent selectivity (approximately 1,000-fold) against all class I...
mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating and promoting activation AGC (protein kinase A/protein G/protein C) family kinases such as Akt B), S6K (p70 ribosomal S6 kinase) SGK (serum glucocorticoid protein kinase). mTORC1 (mTOR complex-1) phosphorylates the hydrophobic motif S6K, whereas mTORC2 SGK. In present paper we describe small molecule Ku-0063794, which inhibits both with an IC50 ∼10 nM, but does not suppress activity 76 other or seven lipid...
AKT is a key node in the most frequently deregulated signaling network human cancer. AZD5363, novel pyrrolopyrimidine-derived compound, inhibited all isoforms with potency of 10 nmol/L or less and phosphorylation substrates cells approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy proliferation 41 182 solid hematologic tumor cell lines 3 μmol/L less. Cell derived from breast cancers showed highest frequency sensitivity. There was significant relationship between presence PIK3CA and/or PTEN...
Computational analysis of phosphoproteomics data predicts the sensitivity leukemia cells to kinase inhibitors.
Small-cell lung cancer (SCLC) has been treated clinically as a homogeneous disease, but recent discoveries suggest that SCLC is heterogeneous. Whether metabolic differences exist among subtypes largely unexplored. In this study, we aimed to determine whether vulnerabilities between can be therapeutically exploited.We performed steady state metabolomics on tumors isolated from distinct genetically engineered mouse models (GEMM) representing the MYC- and MYCL-driven of SCLC. Using genetic...
Abstract Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed selectivity over PARP2, which has been shown play a role in the survival hematopoietic/stem progenitor cells animal models. developed AZD5305 with aim achieving improved clinical efficacy wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide paradigm shift outcomes achieved by first-generation PARPi,...
The PI3K signaling pathway regulates cell growth and movement is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P3. PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, latter producing PI(3,4)P2. PTEN tumor suppressor thought to function primarily as a 3-phosphatase, limiting activation of this pathway. Here we show that also functions PI(3,4)P2 both vitro vivo. major phosphatase Mcf10a cytosol, loss INPP4B, known 4-phosphatase, leads synergistic...
The cyclin dependent kinase (CDK)-retinoblastoma (RB)-E2F pathway plays a critical role in the control of cell cycle estrogen receptor-positive (ER
mTOR is an atypical serine threonine kinase involved in regulating major cellular functions, such as nutrients sensing, growth, and proliferation. part of the multiprotein complexes mTORC1 mTORC2, which have been shown to play critical yet functionally distinct roles regulation processes. Current clinical inhibitors only inhibit complex are derivatives macrolide rapamycin (rapalogs). Encouraging effects observed with rapalogs estrogen receptor-positive (ER(+)) breast cancer patients...
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some failed combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP lack selectivity PARP1 over PARP2 and other 16 family members, we hypothesized that this could contribute toxicity. Recent literature has demonstrated inhibition PARP1–DNA trapping are...
Abstract Background: AZD5305 is a potent, highly selective PARP1 inhibitor and trapper with superior preclinical tolerability, target engagement efficacy vs 1st generation dual PARP1/2 inhibitors (PARPi). This the first report of ongoing Phase 1/2a PETRA (NCT04644068) trial. Methods: Pts advanced breast, ovarian, prostate or pancreatic cancer bearing germline somatic BRCA1/2, PALB2 RAD51C/D mutations received QD PO until disease progression. ECOG PS 0-2 Hb ≥9.0 g/dL were required. Prior...
KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based design approach led the identification of 21, AZD4625, a clinical development candidate for treatment KRASG12C positive tumors. Highlights include quinazoline tethering strategy lock out bio-relevant binding conformation and optimization focused on reduction...
Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kβ activity and specific inhibition PI3Kδ has been shown against human B-cell cancers. We describe discovery optimization a series 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kβ/δ inhibitors, which led clinical candidate 13, also known AZD8186. On basis lower lipophilicity chromen-4-one core compared previously utilized pyrido[1,2-a]pyrimid-4-one core, this compounds displayed high...
mTORC1 [mTOR (mammalian target of rapamycin) complex 1] regulates diverse cell functions. controls the phosphorylation several proteins involved in mRNA translation and specific mRNAs, including those containing a 5'-TOP (5'-terminal oligopyrimidine). To date, most encoded by known mRNAs are translation, such as ribosomal elongation factors. Rapamycin inhibits some functions, whereas mTOR-KIs (mTOR kinase inhibitors) interfere with all them. inhibit overall protein synthesis more strongly...
Abstract Loss of PTEN protein results in upregulation the PI3K/AKT pathway, which appears dependent on PI3Kβ isoform. Inhibitors have potential to reduce growth tumors loss drives tumor progression. We developed a small-molecule inhibitor and PI3Kδ (AZD8186) assessed its antitumor activity across panel cell lines. then explored effects as single agent combination with docetaxel triple-negative breast (TNBC) prostate cancer models. In vitro, AZD8186 inhibited range Sensitivity was associated...
Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" has recently yielded covalent targeting small molecules that bind cysteine create allosteric pocket on GDP-bound RAS, locking it in inactive state. A weak inhibitor at this site was optimized through conformational of a piperazine-quinazoline motif linker modification. Subsequent introduction key methyl...
The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach led the identification 14, AZD4747, a clinical development candidate for treatment KRASG12C-positive tumors, including central nervous system (CNS) metastases. Building on earlier discovery C5-tethered quinazoline AZD4625, excision usually critical pyrimidine ring yielded weak...
Perturbation of hepatocyte growth regulation is associated with a number liver diseases such as fibrosis and cancer. These are mediated by network factors cytokines that regulate the induction proliferation apoptosis. In this study, we have investigated role signaling pathways activated tumor necrosis factor α (TNF-α) epidermal (EGF) in apoptosis induced transforming β 1 (TGF-β ), because physiological believed to spontaneous liver. We show pretreatment (10 ng/mL) EGF or (25 TNF-α can...
Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS TERT) from multi-regional data reason their strong selection should...
Abstract Purpose: We evaluated the properties and activity of AZD9574, a blood–brain barrier (BBB) penetrant selective inhibitor PARP1, assessed its efficacy safety alone in combination with temozolomide (TMZ) preclinical models. Experimental Design: AZD9574 was interrogated vitro for selectivity, PARylation inhibition, PARP-DNA trapping, ability to cross BBB, potential inhibit cancer cell proliferation. In vivo determined using subcutaneous as well intracranial mouse xenograft Mouse, rat,...