Fragment-based drug design facilitates selective kinase inhibitor discovery

Protein kinases inhibitors play vital roles in the treatment of multiple diseases. The problem of selectivity poses a challenge to the development of kinase inhibitors. Fragment-based drug discovery (FBDD) could maximize the kinase–fragment interaction in target kinase subpockets. And the abundant kinase–inhibitor complexes could provide necessary structural information for FBDD to obtain promising selectivity. Understanding kinase–fragment interactions in each kinase subpocket is significant for FBDD. Special interactions targeting subpockets in the back cleft or FP-I/FP-II subpockets of the front cleft are important for selectivity. Development of kinase inhibitors with novel mode of action like allosteric inhibitors via FBDD method is an efficient and potent way to achieve good selectivity. Protein kinases (PKs) are important drug targets, but kinases selectivity poses a challenge to protein kinase inhibitors (PKIs) design. Fragment-based drug discovery (FBDD) has achieved great success in the discovery of highly specific PKIs. It makes full use of kinase–fragment interaction in target kinase subpockets to obtain promising selectivity. However, it’s difficult to understand the complicated kinase–fragment interaction space, and systemic discussion of these interactions is still lacking. Herein, we introduce the advantages of the FBDD strategy in PKIs design. Key features of the selectivity of kinase–fragment interactions are summarized and analyzed. Some promising PKIs are introduced as case studies to help understand the fragment-to-lead (F2L) optimization process. Novel strategies and technologies for FBDD in PKIs discovery are also outlooked. Protein kinases (PKs) are important drug targets, but kinases selectivity poses a challenge to protein kinase inhibitors (PKIs) design. Fragment-based drug discovery (FBDD) has achieved great success in the discovery of highly specific PKIs. It makes full use of kinase–fragment interaction in target kinase subpockets to obtain promising selectivity. However, it’s difficult to understand the complicated kinase–fragment interaction space, and systemic discussion of these interactions is still lacking. Herein, we introduce the advantages of the FBDD strategy in PKIs design. Key features of the selectivity of kinase–fragment interactions are summarized and analyzed. Some promising PKIs are introduced as case studies to help understand the fragment-to-lead (F2L) optimization process. Novel strategies and technologies for FBDD in PKIs discovery are also outlooked. a part of kinase catalytic domain where the adenine group of ATP binds. a type of pocket distinct from orthosteric sites in space and topology. Some perturbations at allosteric sites, such as protein mutations or ligand-binding, can modulate the activity of orthosteric sites. a helix in the N-terminal lobe of the kinase. When it forms a salt bridge with a conserved lysine residue, it is defined as αC-in conformation. Conversely, it is defined as αC-out conformation. a highly conserved motif consisting of three amino acids (Asp-Phe-Gly) at ATP binding site. This motif is involved in the regulation of activation state of protein kinase. a segment consisting of three amino acids. This region is used as an anchor point by ATP and most protein kinase inhibitors. smaller regions of binding sites of proteins that make a great contribution to the binding free energy with ligands. a measurement to characterize the average contribution of each heavy atom to activity. The value of LE is defined by the binding energy of a ligand to its binding partner divided by the number of heavy atoms in this ligand. the logP of a compound, where P is the partition coefficient between n-octanol and water log (Coctanol/Cwater). It is a measure of compound hydrophilicity. a pocket where endogenous ligands and substrates bind. For kinase, it refers to the ATP binding site. a type of heterobifunctional small molecule capable of removing specific unwanted proteins. These molecules are composed of two active domains and a linker structure. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing intracellular proteolysis. a chemical structure that could form covalent bond with protein.