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Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor.
J Med Chem
January 2025
Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
The inhibition of mutant KRAS proteins has emerged as a promising approach for treating KRAS-driven cancers, as evidenced by the clinical success of KRAS G12C inhibitors. KRAS G12D, the most common mutant, promises significant expansion of the addressable patient population; however, the reduced nucleophilicity of aspartate compared to cysteine poses significant challenges in balancing sufficient potency with ADME properties to support oral exposure. Herein, we describe the discovery of KRAS G12D inhibitor (), which achieves oral exposure in nonhuman primate (NHP).
View Article and Find Full Text PDFPreferential Genetic Pathways Lead to Relapses in Adult B-Cell Acute Lymphoblastic Leukemia.
Cancers (Basel)
December 2024
IBSAL, IBMCC, CSIC, Centro de Investigación del Cáncer, University of Salamanca, 37007 Salamanca, Spain.
Adult B-cell acute lymphoblastic leukemia (B-ALL) is characterized by genetic heterogeneity and a high relapse rate, affecting over 40% of adults. However, the mechanisms leading to relapse in adults are poorly understood. Forty-four adult B-ALL patients were studied at both diagnosis and relapse by next-generation sequencing (NGS).
View Article and Find Full Text PDFRobust proteome profiling of cysteine-reactive fragments using label-free chemoproteomics.
Nat Commun
January 2025
Crick-GSK Biomedical LinkLabs, GSK, Gunnels Wood Road, Stevenage, Hertfordshire, UK.
Identifying pharmacological probes for human proteins represents a key opportunity to accelerate the discovery of new therapeutics. High-content screening approaches to expand the ligandable proteome offer the potential to expedite the discovery of novel chemical probes to study protein function. Screening libraries of reactive fragments by chemoproteomics offers a compelling approach to ligand discovery, however, optimising sample throughput, proteomic depth, and data reproducibility remains a key challenge.
View Article and Find Full Text PDFBreaking Solvation Dominance Effect Enabled by Ion-Dipole Interaction Toward Long-Spanlife Silicon Oxide Anodes in Lithium-Ion Batteries.
Nanomicro Lett
December 2024
State Key Laboratory of Space Power-Sources, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, People's Republic of China.
Micrometer-sized silicon oxide (SiO) anodes encounter challenges in large-scale applications due to significant volume expansion during the alloy/de-alloy process. Herein, an innovative deep eutectic electrolyte derived from succinonitrile is introduced to enhance the cycling stability of SiO anodes. Density functional theory calculations validate a robust ion-dipole interaction between lithium ions (Li) and succinonitrile (SN).
View Article and Find Full Text PDFCACHE Challenge #1: Docking with GNINA Is All You Need.
J Chem Inf Model
December 2024
Department of Computational and Systems Biology, University of Pittsburgh, 4200 Fifth Ave, Pittsburgh, Pennsylvania 15260, United States.
We describe our winning submission to the first Critical Assessment of Computational Hit-Finding Experiments (CACHE) challenge. In this challenge, 23 participants employed a diverse array of structure-based methods to identify hits to a target with no known ligands. We utilized two methods, pharmacophore search and molecular docking, to identify our initial hit list and compounds for the hit expansion phase.
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