A5047363846- PI3K/AKT/mTOR signaling in cancer
- Chronic Lymphocytic Leukemia Research
- Enzyme Structure and Function
- Computational Drug Discovery Methods
- Liver Disease Diagnosis and Treatment
- Click Chemistry and Applications
- Animal Nutrition and Physiology
- Diet, Metabolism, and Disease
- Microbial Metabolites in Food Biotechnology
- Chemical Synthesis and Analysis
- Peroxisome Proliferator-Activated Receptors
- Melanoma and MAPK Pathways
- Protein Kinase Regulation and GTPase Signaling
- Cytokine Signaling Pathways and Interactions
- Polysaccharides Composition and Applications
- Vitamin C and Antioxidants Research
- Heat shock proteins research
- Nutrition, Health, and Society Studies
- Microtubule and mitosis dynamics
- Folate and B Vitamins Research
- Monoclonal and Polyclonal Antibodies Research
- Rabbits: Nutrition, Reproduction, Health
- Advanced Breast Cancer Therapies
- Cell Image Analysis Techniques
- Machine Learning in Materials Science
Sanofi (France)
2010-2023
McGill University
1981-1984
Université Laval
1975-1976
Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kβ in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for development PI3Kβ-specific inhibitors treatment cancers. This paper describes discovery 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) optimization this new series active selective pyrimidone indoline amide inhibitors....
Most of the phosphoinositide-3 kinase (PI3K) inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single isoforms differentially control tumorigenesis, and PI3Kβ has emerged as involved tumorigenicity PTEN-deficient tumors. Herein we describe discovery optimization a new series benzimidazole- benzoxazole-pyrimidones small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from one-pot reaction via novel intermediate 1,...
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4–5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC50 = 7.6 μM on Hsp82, the yeast homologue Hsp90). high-resolution X-ray structure shows that 1 binds into an "induced" hydrophobic pocket, 10–15 Å away from...
The Aurora family of serine/threonine kinases is essential for mitosis. Their crucial role in cell cycle regulation and aberrant expression a broad range malignancies have been demonstrated prompted intensive search small molecule inhibitors. Indeed, over 10 them reached the clinic as potential anticancer therapies. We report herein discovery optimization novel series tricyclic molecules that has led to SAR156497, an exquisitely selective A, B, C inhibitor with vitro vivo efficacy. also...
KRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found a third lung, half colorectal and pancreatic cancer cases, is believed be responsible for substantial number deaths. For 30 years, has been subject extensive drug-targeting efforts aimed at targeting protein itself, but also its post-translational modifications, membrane localization, protein-protein interactions downstream signalling pathways. So far, strategies have failed, there are no...
Class IA PI3K pathway activation resulting from PTEN deficiency has been associated with lack of sensitivity melanoma to BRAF kinase inhibitors. Although previous studies have shown synergistic activity when pan-PI3K inhibitors were combined MAPK in the treatment exhibiting concurrent genetic abnormalities, overlapping adverse events patients limit optimal dosing and clinical application. With aim specifically targeting PTEN-deficient cancers minimizing potential for on-target toxicity...
One of the common strategies to identify novel chemical matter in drug discovery consists performing a High Throughput Screening (HTS). However, large amount data generated at dose-response (DR) step an HTS campaign requires careful analysis detect artifacts and correct erroneous datapoints before validating experiments. This which review each DR experiment can be time consuming prone human errors or inconsistencies. AI4DR is system that has been developed for classification curves based on...
Abstract From a screening of 27 106 covalent DNA-encoded compound library, novel KRAS G12C chemical series has been identified. Original hit displayed low µM binding activity to under GDP form associated with k(inact)/Ki 1,03 M-1.s-1, stable electrophilic warhead (T1/2 in 5mM GSH > 24h), +12°C stabilization Delta Tm DSF assay and 3 IC50 value GEF assay, while no detectable GTP WT or G12D form. µM, it also induced significant pERK inhibition H358 KRAS-G12C but not A549 G12S NSCLC cell...
Abstract Abnormal PI3K pathway activation plays a major role in cancer, as result of either RTK or somatic mutations components the pathway, including activating point and amplification PIK3CA gene well loss negative regulatory proteins such PTEN. Most ATP-competitive inhibitors currently clinical development inhibit all class I isoforms: however, several recent reports support isoform-specific inhibitors. In particular, while PI3Kα specific are predicted to growth tumors with mutations,...
From a screening of 27 106 covalent DNA-encoded compound library, novel KRAS G12C chemical series has been identified. Original hit displayed low µM binding activity to under GDP form associated with k(inact)/Ki 1,03 M-1.s-1, stable electrophilic warhead (T1/2 in 5mM GSH > 24h), +12°C stabilization Delta Tm DSF assay and 3 IC50 value GEF assay, while no detectable GTP WT or G12D form. µM, it also induced significant pERK inhibition H358 KRAS-G12C but not A549 G12S NSCLC cell lines. Unique...