A5005093145- PI3K/AKT/mTOR signaling in cancer
- Chronic Lymphocytic Leukemia Research
- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- Lung Cancer Treatments and Mutations
- Microtubule and mitosis dynamics
- Antibiotic Resistance in Bacteria
- Chronic Myeloid Leukemia Treatments
- Peptidase Inhibition and Analysis
- Synthesis and Biological Evaluation
- HER2/EGFR in Cancer Research
- Cancer therapeutics and mechanisms
- RNA and protein synthesis mechanisms
- Quinazolinone synthesis and applications
- Biochemical and Molecular Research
- Cytokine Signaling Pathways and Interactions
- Cell Adhesion Molecules Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Metabolism, Diabetes, and Cancer
- Lung Cancer Research Studies
- Chemotherapy-induced cardiotoxicity and mitigation
- Protein Degradation and Inhibitors
- Bacterial Genetics and Biotechnology
- Chemical Synthesis and Analysis
- IL-33, ST2, and ILC Pathways
Sunesis (United States)
2004-2012
Small molecule inhibitors that target the phosphatidylinositol 3-kinase (PI3K) signaling pathway have received significant interest for treatment of cancers. The class I isoform PI3Kα is most commonly associated with solid tumors via gene amplification or activating mutations. However, demonstrating both PI3K and mutant specificity remained elusive. Herein, we describe optimization characterization a series benzoxazepin-oxazolidinone ATP-competitive which also induce selective degradation...
LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation immunological synapse, augmentation receptor signaling. The increase ICAM-1 expression levels conjunctival epithelial cells acinar was observed animal models patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule antagonists could be an effective topical...
The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest discovering selective inhibitors for use treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor Jak2. Optimization lead compounds 7a-b and 8 this chemical series activity against Jak2, selectivity other Jak family kinases, good vivo pharmacokinetic properties 7j. In SET2 xenograft model that...
Abstract PIK3CA is one of the most frequently mutated oncogenes; p110a protein it encodes plays a central role in tumor cell proliferation. Small-molecule inhibitors targeting PI3K catalytic subunit have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and manageable safety profile patients PIK3CA-mutant breast cancer. However, preclinical shown that pathway inhibition releases negative feedback activates receptor tyrosine kinase signaling, reengaging...
Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions exon 19, increase EGFR-driven cell proliferation and survival are correlated with impressive responses to EGFR inhibitors erlotinib gefitinib in nonsmall lung cancer patients. Approximately 60% of acquired resistance these agents is driven by a single secondary mutation specifically substitution gatekeeper residue threonine-790 methionine (T790M). Due dose-limiting toxicities...
Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation the gatekeeper residue, means that clinical responses only last for 8–14 months. Addressing this unmet medical need requires agents can target both most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750)...
Herein we report the discovery of C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent orally bioavailable JAK1 inhibitors with selectivity over JAK2. The inhibitor 4 exhibited not only improved potency relative unsubstituted compound 3 but also notable vs JAK2 (20-fold >33-fold in biochemical cell-based assays, respectively). Features X-ray structures complex both are delineated. Efforts improve vitro vivo ADME properties while maintaining described,...
A one-pot procedure for the conversion of aromatic and heteroaromatic 2-nitroamines into bicyclic 2H-benzimidazoles is described. The employs formic acid, iron powder, an additive such as NH4Cl to reduce nitro group effect imidazole cyclization with high-yielding conversions generally within one two hours. compatibility a wide range functionality demonstrates general utility this procedure.
The rapid advancement of a series noncovalent inhibitors T790M mutants EGFR is discussed. optimization pyridone 1, nonselective high-throughput screening hit, to potent molecules with high levels selectivity over wtEGFR and the broader kinome described herein.
Inhibitors targeting the activating mutants of epidermal growth factor receptor (EGFR) have found success in treatment EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) inhibitor binding site has been linked to acquired resistance against those first generation therapeutics. Herein, we describe lead optimization a series reversible, pan-mutant (L858R, del746-750, T790M/L858R, and T790M/del746-750) inhibitors. By use noncovalent double (T790M/L858R selective...
Despite increasing evidence suggesting that antibiotic heteroresistance can lead to treatment failure, the significance of this phenomena in clinic is not well understood, because many clinical susceptibility testing approaches lack resolution needed reliably classify heteroresistant strains. Here we present G0790, a new globomycin analog and potent inhibitor Escherichia coli type II signal peptidase LspA. We demonstrate addition previously known mechanisms resistance LspA inhibitors,...
Acinetobacter baumannii is a clinically important, predominantly health care–associated gram-negative bacterium with high rates of emerging resistance worldwide. Given the urgent need for novel antibacterial therapies against A. , we focused on inhibiting lipoprotein biosynthesis, pathway that essential envelope biogenesis in bacteria. The natural product globomycin, which inhibits type II signal peptidase prolipoprotein (LspA), ineffective wild-type clinical isolates due to its poor...
Abstract The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway is a major regulator tumor cell growth, proliferation and survival. Dysregulation the PI3K/Akt/mTOR through multiple mechanisms has been described in solid malignancies, including activating transforming “hotspot” mutations as well amplification PIK3CA that encodes p110 alpha subunit PI3K. Hotspot mutation are frequently observed breast cancer with prevalence...