Eloísa Jiménez Núñez
A5061657919- Bioactive Compounds and Antitumor Agents
- Synthesis and biological activity
- Pharmacological Effects of Natural Compounds
- Cancer-related Molecular Pathways
- Hippo pathway signaling and YAP/TAZ
- DNA Repair Mechanisms
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Ubiquitin and proteasome pathways
- PARP inhibition in cancer therapy
- Vitamin K Research Studies
- Protein Tyrosine Phosphatases
- Carcinogens and Genotoxicity Assessment
- Cell death mechanisms and regulation
- RNA modifications and cancer
- Genetic factors in colorectal cancer
- Enzyme function and inhibition
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
Novartis (Switzerland)
2022-2024
Novartis Institutes for BioMedical Research
2022-2023
Bayer (Germany)
2023
Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor GDP-bound that forms novel interactions with the switch II pocket. potently inhibits KRASG12C-driven cellular signaling demonstrates selective antiproliferative in cell lines, including those G12C/H95 double mutations. In vivo, induces AUC...
The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available pharmacologic agents bind into lipid pocket TEAD, targeting indirectly via allosteric changes. However, consequences a direct pharmacological disruption interface between and TEADs remain largely unexplored. Here, we present IAG933 its analogs as potent first-in-class selective disruptors with suitable properties to enter clinical trials. Pharmacologic abrogation all...
Abstract The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens 1–6 . Despite advances treatment immune checkpoint inhibitors 7–10 , there is an unmet need the of MSI cancers 11–14 Here we report structural, biochemical, cellular and pharmacological characterization clinical-stage inhibitor HRO761, which through innovative hit-finding lead-optimization strategy. HRO761 potent,...
Abstract The YAP-TEAD protein-protein interaction (PPI) is a critical event known to mediate YAP oncogenic functions downstream of the Hippo pathway. Current advanced pharmacological agents which aim at inhibiting function do so by engaging into lipid pocket TEAD. Thereby consequences direct disruption interface and TEADs remain unexplored. Here we report identification IAG933, first molecule able potently directly disrupt YAP/TAZ-TEADs PPI with suitable properties enter in clinical trial....
Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but thought play only minor role in hemostasis so that its inhibition may allow for decoupling efficacy bleeding time prolongation. Herein, we report our major efforts identify an orally bioavailable, reversible FXIa inhibitor. Using protein structure-based de novo design approach, identified novel micromolar hit with physicochemical...
Abstract The RecQ DNA helicase WRN was identified as a synthetic lethal target in tumors with microsatellite instability (MSI) by several genetic screens. Despite recent advances the treatment of MSI immune checkpoint inhibitors, significant proportion patients still fails to respond or relapses after single agent anti-PD1 combination plus anti-CTLA4 treatments. We present biochemical, cellular and pharmacological characterization first potent selective inhibitor, HRO761. show that HRO761 is...
Abstract RAS is the most frequently mutated oncogene in cancer. KRAS G12C mutations are prevalent lung adenocarcinoma (~13%) and colorectal (~4%), occur less commonly other solid tumor malignancies. First generation KRASG12C inhibitors show anti-tumor activity early phase clinical trials. However, emergence of resistance, mediated at least part by gene that disrupt inhibitor binding reactivation downstream pathways, limit duration response. Here we report identification JDQ443 (NVP-JDQ443),...
Abstract Colorectal carcinoma (CRC) as well other indications that have lost competence in mismatch repair and a phenotype known microsatellite instability (MSI), remain significant unmet medical need. Large-scale functional genomics screens across cell line panels identified the Werner Syndrome RecQ helicase (WRN) being synthetic lethal with MSIhigh cancers. Thus, WRN inhibitors may offer new therapeutic avenue We report preclinical characteristics of HRO761, first-in-class, highly potent...
<div>Abstract<p>Covalent inhibitors of KRAS<sup>G12C</sup> have shown antitumor activity against advanced/metastatic <i>KRAS<sup>G12C</sup></i>-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor GDP-bound that forms novel interactions with the switch II pocket. potently inhibits KRAS<sup>G12C</sup>-driven cellular signaling...
<div>Abstract<p>Covalent inhibitors of KRAS<sup>G12C</sup> have shown antitumor activity against advanced/metastatic <i>KRAS<sup>G12C</sup></i>-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor GDP-bound that forms novel interactions with the switch II pocket. potently inhibits KRAS<sup>G12C</sup>-driven cellular signaling...
Supplementary Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, Selective Covalent Oral Inhibitor KRAS<sup>G12C</sup>
Supplementary Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, Selective Covalent Oral Inhibitor KRAS<sup>G12C</sup>
Supplementary Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, Selective Covalent Oral Inhibitor KRAS<sup>G12C</sup>
Supplementary Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, Selective Covalent Oral Inhibitor KRAS<sup>G12C</sup>
Supplementary Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, Selective Covalent Oral Inhibitor KRAS<sup>G12C</sup>
Supplementary Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, Selective Covalent Oral Inhibitor KRAS<sup>G12C</sup>