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Targeted Covalent Modification Strategies for Drugging the Undruggable Targets.
Chem Rev
January 2025
Graduate School of Engineering, Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
The term "undruggable" refers to proteins or other biological targets that have been historically challenging to target with conventional drugs or therapeutic strategies because of their structural, functional, or dynamic properties. Drugging such undruggable targets is essential to develop new therapies for diseases where current treatment options are limited or nonexistent. Thus, investigating methods to achieve such drugging is an important challenge in medicinal chemistry.
View Article and Find Full Text PDFRoutes to molecular glue degrader discovery.
Trends Biochem Sci
January 2025
School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China. Electronic address:
Molecular glue degraders (MGDs) represent a unique class of targeted protein degradation (TPD) modalities. By facilitating protein-protein interactions between E3 ubiquitin ligases and neo-substrates, MGDs offer a novel approach to target previously undruggable or insufficiently drugged disease-causing proteins. Here, we present an overview of recently reported MGDs, highlighting their diverse mechanisms, and we discuss mechanism-based strategies to discover new MGDs and neo-substrates.
View Article and Find Full Text PDFDrugging p53: Barriers, Criteria, and Prospects.
Cancer 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 PDFStructural perspectives on recent breakthrough efforts toward direct drugging of RAS and acquired resistance.
Front Oncol
May 2024
Chemical Biology Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.
The Kirsten rat sarcoma viral oncoprotein homolog (KRAS) is currently a primary focus of oncologists and translational scientists, driven by exciting results with KRAS-targeted therapies for non-small cell lung cancer (NSCLC) patients. While KRAS mutations continue to drive high cancer diagnosis and death, researchers have developed unique strategies to target KRAS variations. Having been investigated over the past 40 years and considered "undruggable" due to the lack of pharmacological binding pockets, recent breakthroughs and accelerated FDA approval of the first covalent inhibitors targeting KRAS, have largely sparked further drug development.
View Article and Find Full Text PDFDrugging the undruggable: Advances in targeting KRAS signaling in solid tumors.
Int Rev Cell Mol Biol
April 2024
Department of Genetics, Albert Einstein College of Medicine, New York, NY, United States. Electronic address:
Cancer remains the leading cause of global mortality, prompting a paradigm shift in its treatment and outcomes with the advent of targeted therapies. Among the most prevalent mutations in RAS-driven cancers, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations account for approximately 86% of cases worldwide, particularly in lung, pancreatic, and colon cancers, contributing to poor prognosis and reduced overall survival. Despite numerous efforts to understand the biology of KRAS mutants and their pivotal role in cancer development, the lack of well-defined drug-binding pockets has deemed KRAS an "undruggable" therapeutic target, presenting significant challenges for researchers and clinicians alike.
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