A5066035783- Protein Kinase Regulation and GTPase Signaling
- Plant-based Medicinal Research
- Microtubule and mitosis dynamics
- Historical Studies on Reproduction, Gender, Health, and Societal Changes
- Melanoma and MAPK Pathways
- Medical History and Innovations
- Cancer-related Molecular Pathways
- Biochemical and Molecular Research
- PI3K/AKT/mTOR signaling in cancer
- Sports Analytics and Performance
- Animal testing and alternatives
- Cancer Research and Treatments
- Hormonal and reproductive studies
- Hormonal Regulation and Hypertension
- Sport and Mega-Event Impacts
- Biomedical Research and Pathophysiology
- Vascular Malformations and Hemangiomas
- interferon and immune responses
- Innovative Teaching and Learning Methods
- Cancer Genomics and Diagnostics
- Cancer Cells and Metastasis
- Sexual Differentiation and Disorders
- Lysosomal Storage Disorders Research
- Enzyme Structure and Function
- Ubiquitin and proteasome pathways
University of Birmingham
2024
AstraZeneca (United Kingdom)
2017-2023
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...
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...
Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein TTK, are in different stages clinical development. However, cell response to SAC abrogation is poorly understood there no markers for patient selection.A panel 53 tumor lines origins was used. The effects drugs were analyzed by MTT flow cytometry. Copy number status determined FISH Q-PCR; mRNA expression nCounter RT-Q-PCR Western blotting. CRISPR-Cas9 technology used...
Abstract AZD4625 is a potent, selective, and orally bioavailable inhibitor of oncogenic KRASG12C as demonstrated in cellular assays vivo preclinical cell line–derived patient-derived xenograft models. In vitro have shown selective binding inhibition the mutant isoform, which carries glycine to cysteine mutation at residue 12, with no wild-type RAS or isoforms carrying non-KRASG12C mutations. The pharmacology shows that it has potential provide therapeutic benefit patients cancer either...
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Supplementary Figure from AZD4625 is a Potent and Selective Inhibitor of KRAS<sup>G12C</sup>
Supplementary Data from AZD4625 is a Potent and Selective Inhibitor of KRAS<sup>G12C</sup>
Supplementary Figure from AZD4625 is a Potent and Selective Inhibitor of KRAS<sup>G12C</sup>
Supplementary Data from AZD4625 is a Potent and Selective Inhibitor of KRAS<sup>G12C</sup>
<div>Abstract<p>AZD4625 is a potent, selective, and orally bioavailable inhibitor of oncogenic KRAS<sup>G12C</sup> as demonstrated in cellular assays <i>in vivo</i> preclinical cell line–derived patient-derived xenograft models. <i>In vitro</i> have shown selective binding inhibition the mutant isoform, which carries glycine to cysteine mutation at residue 12, with no wild-type RAS or isoforms carrying non-KRAS<sup>G12C</sup>...
<div>Abstract<p>AZD4625 is a potent, selective, and orally bioavailable inhibitor of oncogenic KRAS<sup>G12C</sup> as demonstrated in cellular assays <i>in vivo</i> preclinical cell line–derived patient-derived xenograft models. <i>In vitro</i> have shown selective binding inhibition the mutant isoform, which carries glycine to cysteine mutation at residue 12, with no wild-type RAS or isoforms carrying non-KRAS<sup>G12C</sup>...
Abstract Most preclinical oncology studies (xenograft, PDX, GEMMS) involve monitoring tumour growth rates, measuring them with callipers, and calculating the volume. Volume is calculated from width length to estimate a 3D volume directly used assess treatment efficacy. Although this technique useful, it unable accurately non-uniformly shaped or very small tumours introduces systematic bias by assuming that present spheroid shape. Furthermore callipers do not inform of condition, which...
Abstract ERK1/2 is a key protein in the MAPK pathway, regulating phenotypes such as proliferation and migration. Upstream mutations (e.g., KRAS non-small-cell lung (NSCLC)) can cause pathway to become constitutively activated, driving tumor growth. AZD0364 potent, selective inhibitor of ERK's kinase activity against its cytosolic substrate p90RSK. It currently preclinical development, where it has shown dose-dependent, anti-tumor xenograft models KRAS-mutant NSCLC, including Calu-6 (where...