About this Research Topic
For over a century, covalent drugs have been employed in disease treatment. Covalent drugs include a mild reactive functional group that forms a covalent bond with protein targets, providing additional affinity beyond the non-covalent interactions typically involved in drug binding. Covalent binding enables potent and selective inhibition of target proteins, as demonstrated by covalent inhibitors of epidermal growth factor receptor (EGFR) and Bruton’s tyrosine kinase (BTK) used in cancer treatment. The discovery of KRAS (G12C) inhibitors particularly validates the use of covalent screening technologies, which have significantly advanced and become more widespread over the past decade. In addition to enzymes, covalent drugs are now being developed to target non-enzymatic proteins, opening new possibilities for therapeutic intervention.
The Research Topic aims to provide a foundational basis for the development of additional, novel protein inhibitors. The primary objective is to showcase the recent advancements in discovering covalent inhibitors, particularly those targeting Protein Tyrosine Kinases (PTKs), for treating various disorders associated with PTK overexpression. Moreover, modifying the structures of existing compounds has proven to be an effective strategy for developing more potent therapeutic agents. Notably, the discovery of inhibitors for previously undruggable targets, such as KRAS (G12C), offers new opportunities for addressing disorders linked to the overexpression of proteins, including cancers and neurodegenerative diseases.
We welcome Original Research, Review, Mini Review and Perspective articles on themes including, but not limited to:
• Current advances in novel strategies for covalent inhibitors drug discovery.
• Schematic diagram showing the rational design of the proposed compounds.
• Extensive in vitro studies, including, but not limited to, enzyme inhibition data and cytotoxicity assays.
• Time dependent inhibition assays for the most potent compound.
• Enzyme inhibition selectivity assays.
• Analysis of structure-activity relationships (SAR).
• In silico studies and pharmacokinetic (PK) studies.
• Mechanistic studies detailing how covalent inhibitors interact with their targets.
• Novel reactive groups and chemical probes in covalent inhibitors.
• Structural biology studies, including X-ray crystallography, NMR, or cryo-EM, for understanding covalent inhibitor binding.
• Demonstration of the study’s future directions.
The Research Topic aims to provide a foundational basis for the development of additional, novel protein inhibitors. The primary objective is to showcase the recent advancements in discovering covalent inhibitors, particularly those targeting Protein Tyrosine Kinases (PTKs), for treating various disorders associated with PTK overexpression. Moreover, modifying the structures of existing compounds has proven to be an effective strategy for developing more potent therapeutic agents. Notably, the discovery of inhibitors for previously undruggable targets, such as KRAS (G12C), offers new opportunities for addressing disorders linked to the overexpression of proteins, including cancers and neurodegenerative diseases.
We welcome Original Research, Review, Mini Review and Perspective articles on themes including, but not limited to:
• Current advances in novel strategies for covalent inhibitors drug discovery.
• Schematic diagram showing the rational design of the proposed compounds.
• Extensive in vitro studies, including, but not limited to, enzyme inhibition data and cytotoxicity assays.
• Time dependent inhibition assays for the most potent compound.
• Enzyme inhibition selectivity assays.
• Analysis of structure-activity relationships (SAR).
• In silico studies and pharmacokinetic (PK) studies.
• Mechanistic studies detailing how covalent inhibitors interact with their targets.
• Novel reactive groups and chemical probes in covalent inhibitors.
• Structural biology studies, including X-ray crystallography, NMR, or cryo-EM, for understanding covalent inhibitor binding.
• Demonstration of the study’s future directions.
Keywords: Covalent inhibitors, Protein tyrosine kinases, Cancer, Neurodegenerative disorders, Undruggable proteins
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
