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http://dx.doi.org/10.1038/s43018-025-00914-5 | DOI Listing |
Biochem Biophys Res Commun
May 2025
Department of Pharmacology, Novel Drug Discovery and Development (NDDD), Lupin Limited, Survey No. 46A/47A, Village Nande, Taluka Mulshi, Pune, 412115, Maharashtra, India.
Development of mutant specific KRAS inhibitors validated KRAS as a 'druggable' target. However, excellent initial efficacy was eventually overshadowed by failure to exhibit sustained clinical response, primarily due to acquired resistance. Some targeted therapies like SOS1, SHP2, and MEK inhibitors, in combination with mutant KRAS G12C inhibitors (G12Ci), are currently under clinical investigation with evidences of improving efficacy.
View Article and Find Full Text PDFNat Cancer
February 2025
Department of Pharmacology, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
Cancers (Basel)
January 2025
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
aberrations in head and neck squamous cell carcinoma (HNSCC) remain clinically inactionable today. Here, we investigated the clinical significance and potential druggability of genomic aberrations in HNSCC. Notably, HPV(-)HNSCC patients bearing the unique HNSCC-prevalent -A159V hotspot mutation, P29S hotspot and G-box domain mutations, and copy number increases all displayed dismal overall survival (TCGA-HNSCC).
View Article and Find Full Text PDFJ Biol Chem
January 2025
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Electronic address:
While ATP-site inhibitors for protein-tyrosine kinases are often effective drugs, their clinical utility can be limited by off-target activity and acquired resistance mutations due to the conserved nature of the ATP-binding site. However, combining ATP-site and allosteric kinase inhibitors can overcome these shortcomings in a double-drugging framework. Here we explored the allosteric effects of two pyrimidine diamines, PDA1 and PDA2, on the conformational dynamics and activity of the Src-family tyrosine kinase Hck, a promising drug target for acute myeloid leukemia.
View Article and Find Full Text PDFCancer Discov
November 2024
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Pharmacologically targeting tumor suppressors necessitates an unprecedented strategy of restoring, rather than conventionally inhibiting, protein function, and p53, the most commonly mutated protein in cancer, has thus remained undruggable. In this study, we address long-standing misconceptions in the field and gaps in the scientific logic for a p53 function-restoration strategy, identify four barriers for drugging mutant p53, and accordingly propose effectiveness evaluation criteria, clinical-translating norms, and prospects for mutant p53 rescue compounds.
View Article and Find Full Text PDF