A5049708947- Gastrointestinal Tumor Research and Treatment
- Platelet Disorders and Treatments
- PI3K/AKT/mTOR signaling in cancer
- Advanced Breast Cancer Therapies
- Protein Degradation and Inhibitors
- Sarcoma Diagnosis and Treatment
- Cancer Mechanisms and Therapy
- Peptidase Inhibition and Analysis
- Cancer therapeutics and mechanisms
- DNA Repair Mechanisms
- Estrogen and related hormone effects
- Multiple Myeloma Research and Treatments
- Cancer Treatment and Pharmacology
- Cell Adhesion Molecules Research
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- Melanoma and MAPK Pathways
- Click Chemistry and Applications
- Immune Cell Function and Interaction
- Angiogenesis and VEGF in Cancer
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
- Hippo pathway signaling and YAP/TAZ
- Protein Kinase Regulation and GTPase Signaling
- Microtubule and mitosis dynamics
AstraZeneca (United States)
2013-2024
AstraZeneca (United Kingdom)
2007-2024
Kala Pharmaceuticals (United States)
2024
Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on observation majority of are deficient G1-DNA damage checkpoint pathway reliance S G2 checkpoints for DNA repair survival. regulated by kinase 1, serine/threonine is activated response damage; thus, inhibition 1 signaling impairs increases tumor death. Normal tissues, however,...
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...
KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances targeted therapy have shown great promise, effective targeting remains elusive, and concurrent alterations tumor suppressors render KRAS-mutant tumors even more resistant to existing therapies. Contributing the refractoriness are immunosuppressive mechanisms, such as increased presence suppressive regulatory T cells (Treg) elevated expression inhibitory receptor PD-1 on tumor-infiltrating...
Most lung cancer patients with metastatic eventually relapse drug-resistant disease following treatment and EGFR mutant is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cell lines, revealed the landscape of pathways that cause resistance inhibitors osimertinib gefitinib cancer. Among most recurrent were those regulate Hippo pathway. Following a subpopulation cells are able survive over time develop stable resistance. These...
The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to in vivo MAT2a tool inhibitor is discussed. structure-based drug discovery approach, aided relative binding free energy calculations, resulted AZ'9567 (21), a potent vitro with excellent preclinical pharmacokinetic properties. This showed selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both and vivo, providing further evidence support the utility inhibitors...
Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results cell cycle arrest, allowing sufficient time for repair. Agents lead abrogation of such checkpoints have potential increase the efficacy compounds as chemo- radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified inhibitors by high throughput screening. A structure-based approach is described using crystal structures JNK1 complex with 1 2 CHK1-3b complex. The ribose binding pocket was targeted...
While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by application targeted tyrosine kinase inhibitors capable inhibiting KIT-driven proliferation, diverse mutations to this drive resistance established therapies. Here we describe identification potent pan-KIT mutant that can be dosed without being limited tolerability issues seen with multitargeted agents. This effort focused on and optimization an existing scaffold through use structure-based design....
MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from and ATP. Tumors bearing co-deletion of p16 MTAP genes have been shown to be sensitive inhibition, making it an attractive target for treatment MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in known allosteric site. By use structure-guided design systematic SAR exploration, were elaborated through merging growing...
Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy specific PI3Kβ/δ inhibitor AZD8186. We identified a subset DLBCL models within activated B-cell–like (ABC) and germinal center (GCB) were sensitive to AZD8186 treatment. On molecular level,...
Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or T790M resistance mutations. While patients treated osimertinib show clinical benefit, disease progression and drug common. Emergence of de novo acquired from a tolerant persister (DTP) population is one mechanism proposed to explain on other targeted therapies. Here we profiled DTPs using RNA-seq...
B-Raf represents an attractive target for anticancer therapy and the development of small molecule inhibitors has delivered new therapies metastatic melanoma patients. We have discovered a novel class molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro vivo. Investigations into structure-activity relationships series are presented along with efforts to improve upon cellular potency, solubility, pharmacokinetic profile. Compounds selectively inhibited showed preferential...
Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 from different chemical scaffolds have been developed and evaluated in clinical trials combination with chemotherapeutics radiation treatment. Scaffold morphing thiophene carboxamide ureas (TCUs), such as AZD7762 (1) a related series triazoloquinolines (TZQs), led to identification fused-ring bicyclic inhibitors,...
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....
Abstract Background: PRMT5 is an epigenetic enzyme that catalyzes symmetric di-methylation of arginine (SDMA) multiple substrates regulate biological processes including RNA splicing and cell cycle. The role in controlling chromatin accessibility has been investigated some cancer contexts, but its non-small lung (NSCLC) global regulation not known. AstraZeneca developed MTA-cooperative inhibitor (AZD3470) selectively inhibits MTAP-null tumors currently Phase I clinical trial (NCT06130553,...
AZD3229 demonstrates pan-KIT/PDGFRα activity in several preclinical models and is a promising agent for the treatment of GIST.
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...
The tumour suppressor p16/CDKN2A and the metabolic gene, methyl-thio-adenosine phosphorylase (MTAP), are frequently co-deleted in some of most aggressive currently untreatable cancers. Cells with MTAP deletion vulnerable to inhibition enzyme, methionine-adenosyl transferase 2A (MAT2A), protein arginine methyl (PRMT5). This synthetic lethality has paved way for rapid development drugs targeting MAT2A/PRMT5 axis. MAT2A its liver- pancreas-specific isoform, MAT1A, generate universal donor...
The emergence of secondary mutations is a cause resistance to current KIT inhibitors used in the treatment patients with gastrointestinal stromal tumors (GIST). AZD3229 selective inhibitor wild-type and wide spectrum primary seen GIST. objective this analysis establish pharmacokinetic-pharmacodynamic (PKPD) relationship range mouse GIST tumor models harboring mutations, benchmark against other inhibitors.A PKPD model was developed for linking plasma concentrations inhibition phosphorylated...
Abstract Cyclin-dependent kinase 9 (Cdk9) is a serine/threonine that regulates elongation of transcription through phosphorylation RNA polymerase II at serine 2 (pSer2-RNAPII). Mcl1, an anti-apoptotic protein has been linked to increased survival and chemotherapy resistance in various cancers, can be indirectly modulated transient inhibition Cdk9 due it having short-lived transcript being labile protein. Transient Cdk9, therefore, represents potential therapeutic opportunity tumors dependent...
Abstract The Pim serine/threonine kinase family is composed of three highly homologous members; Pim-1, Pim-2 and Pim-3, identified by the ability prototype member Pim-1 to drive lymphomagenesis in mice. Upregulation observed leukemias lymphomas, including AML, NHL CLL, highlighting potential these kinases as therapeutic targets indications. Overexpression or Pim-3 has also been prostate, pancreatic, gastric, bladder hepatocellular cancers. are downstream effectors many cytokine growth factor...