PROTACting the kinome with covalent warheads

• Published in: Drug discovery today Vol. 28; no. 1; p. 103417
• Main Authors: Chatterjee, Deep Rohan, Kapoor, Saumya, Jain, Meenakshi, Das, Rudradip, Chowdhury, Moumita Ghosh, Shard, Amit
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2023
• Subjects: Covalent inhibitors; E3 ligase; Kinase; PROTACs; Proteins - metabolism; Proteolysis; Targeted kinase degradation; PROTACs; E3 ligase; Targeted kinase degradation; Covalent inhibitors; Kinase
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2022.103417

[Display omitted] •A brief prologue of PROTACs targeting human kinases is focused upon.•Advantages of PROTACs over traditional small molecule drugs.•Role of covalent warheads incorporated in various PROTAC moieties.•Insights into recent trends to fast-track PROTACs synthesis and screening.•Future trends and glimpses of the modern heterobifunctional moieties branching off from PROTACs. The dawn of targeted degradation using proteolysis-targeting chimeras (PROTACs) against recalcitrant proteins has prompted numerous efforts to develop complementary drugs. Although many of these are specifically directed against undruggable proteins, there is increasing interest in small molecule-based PROTACs that target intracellular pathways, and some have recently entered clinical trials. Concurrently, small molecule-based PROTACs that target protumorigenic pathways in cancer cells, the tumor microenvironment (TME), and angiogenesis have been found to have potent effects that synergize with the action of antibodies. This has led to the augmentation of PROTACs with variable substitution patterns. Several combinations with small molecules targeting undruggable proteins are now under clinical investigation. In this review, we discuss the recent milestones achieved as well as challenges encountered in this area of drug development, as well as our opinion on the best path forward.