Derisking Idiosyncratic Toxicity Concerns with a Covalent Modifying Drug: Retrospective analysis with the pan-ErbB Receptor Tyrosine Kinase Inhibitor and Clinical Candidate (CI-1033, Canertinib)

The design of controlled target-specific covalent enzyme inhibitors is conceptually very attractive given the increased biochemical efficiency associated with an irreversible mechanism, which can lead to high therapeutic margins. From a practical standpoint, however, this is hard to achieve because of the difficulty in striking the “right” balance between target covalent binding and indiscriminant reactivity with proteins, DNA, and glutathione that can cause acute or delayed immune-mediated toxicity (e.g., drug allergy and/or hypersensitivity). Against this backdrop, ~ 74 enzymes that are inhibited by marketed drugs, 19 are inactivated via selective covalent modification with little to no toxicity. A likely reason for this phenomenon may be the poor intrinsic chemical reactivity of the “warhead” towards nucleophiles under physiological conditions but yet upon appropriate positioning within the active site of the target protein, the electrophilic functionality selectively reacts with an active site amino acid nucleophile. As such, there is little, if any, information available on such attributes on the approved or investigational drugs. Consequently, from a drug discovery perspective, there is currently no experimental paradigm to systematically derisk the toxicity potential with covalent inhibitors in programs that adopt such strategies. CI-1033 (Canertinib) is a pan-ErbB receptor tyrosine kinase inhibitor, which irreversibly binds to the kinase through its electrophilic acrylamide motif. CI-1033 also was an advanced clinical candidate for the treatment of advanced non-hematological cancers. In this retrospective analysis we examine the disposition of CI-1033 in animals and humans with a particular emphasis on its potential for indiscriminant alkylation (relative to its pharmacology and overall elimination pathways). The approaches described herein could be applied in drug discovery programs attempting to pursue covalent modifiers.