We have seen in this chapter that some cancer drugs exert their cytotoxic effects by forming covalent bonds with their target (e.g., the reaction of mechlorethamine with DNA bases). A number of well-known drugs including aspirin and omeprazole work by covalent modification of their targets. In most such cases, however, the reactive nature of the drug was not appreciated at the time of its discovery or approval. In modern drug discovery, the idea of intentionally designing drugs to react with their target is controversial. Avoiding covalent modification of the target is probably advisable in the case of chronic conditions (e.g., pain, autoimmune disease) where a drug must be administered over years or even a lifetime. In the case of more acute conditions such as cancer or infection, however, the potential benefits of covalent drugs may outweigh the risks.

One area where the idea of covalent drugs has garnered attention is the treatment of cancer, and specifically in the development of kinase inhibitors. Kinases mediate a wide variety of cellular signaling events by transferring a phosphate group to specific oxygen atom(s) on their substrate(s). When a kinase is aberrantly activated or inactivated, the resulting effects on signaling pathways can result in the unrestrained cell growth that is characteristic of cancer. The first kinase inhibitor approved to treat cancer was imatinib (Gleevec^®). The success of this drug in treating certain kinase-driven cancers demonstrated the potential of kinase inhibition as a new therapeutic approach in oncology. However, producing selective kinase inhibitors can be challenging because most kinase inhibitors target the ATP-binding site, which is quite similar across the roughly 500 known human kinases. One approach to improve selectivity has been to design kinase inhibitors to react with the thiol (–SH) group of specific cysteine residues present only in a subset of kinases. Two recently approved kinase inhibitor drugs that were intentionally designed to react with their kinase targets are ibrutinib (Imbruvica^®) and afatinib (Gilotrif^®). Both drugs possess a side chain with an electrophilic Michael acceptor (Figure 6.33).

Figure 6.33 Structures of irreversible kinase inhibitors afatinib and ibrutinib. Each compound bears an electrophilic side chain (shown in red) intended to react with a nucleophilic cysteine residue on the kinase target.

Afatinib is an irreversible inhibitor of a family of membrane-bound receptor tyrosine kinases that includes EGFR and HER2. Mutations in EGFR are implicated in some head and neck tumors while overproduction of HER2 is associated with some breast cancers. Afatinib binds in the ATP-binding site of EGFR with its electrophilic side chain positioned in close proximity to cysteine-797. Afatinib targets an analogous cysteine residue (Cys805) on HER2. With the electrophilic drug and nucleophilic cysteine thiol in close proximity, a nucleophilic addition (Michael reaction) can occur (Figure 6.34). Note that non-covalent binding of afatinib to EGFR (or HER2) must occur prior to the subsequent covalent reaction; the initial non-covalent binding is what brings the reacting groups into proximity. This proximity effect may explain why such drugs react selectively with specific cysteine residues on their target and do not react randomly with any exposed cysteine thiol.

Figure 6.34 Top: Michael addition reaction between the electrophilic side chain of afatinib and the nucleophilic thiol of Cys797 on the receptor tyrosine kinase EGFR. Bottom: Two images created from the X-ray crystal structure of EGFR with afatinib bound. The covalent bond between afatinib and Cys797 is apparent in the close-up image of the ATP-binding site (bottom, right).

Ibrutinib is an irreversible inhibitor of a different kinase, Bruton’s tyrosine kinase (BTK), and is currently approved to treat mantel cell lymphoma and chronic lymphocytic leukemia. The drug binds covalently to Cys-481 in the ATP-binding site of BTK, resulting in potent inhibition of kinase activity. Initial indications are that ibrutinib is well tolerated and effective in CLL patients that have typically had a poor prognosis, such as those with relapsing disease. Time will tell if the success of new drugs like ibrutinib and afatinib leads to greater interest in drugs designed to form covalent bonds with their biological targets.

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