Irreversible kinase inhibitors

Cohen MS, Zhang C, Shokat KM, Taunton J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science 2005 308 1318-1321. 

Figure 10.1 Representative examples of irreversible kinase inhibitors for the treatment of solid tumors and hematological malignancies.

Two of the small molecule inhibitors, gefitinib (166, EGF receptor kinase inhibitor) and imat-inib (167, Bcr-Abl receptor kinase inhibitor), have reached the market. Although many of the starting leads for kinase inhibitors were obtained by random screening approaches, further medicinal chemistry was aided by the availability of a number of crystal structures and other modelling approaches The design of irreversible... 

The quinoline-based tyrosine kinase inhibitor pelitinib (31-11) incorporates a Michael acceptor function in the side chain that can form a covalent bond with a nucleophile on the target enzyme. Such an interaction would result in the irreversible inhibition of the target kinase. Reaction of aniline (31-1) with DMF acetal leads to the addition of a carbon atom to aniline nitrogen in the form of an amidine (31-2). This intermediate is next reacted with nitric in acetic acid to form the nitrated... 

Because the T790M mutation affects the ability of reversible TKIs to bind to EGFR, it follows that irreversible inhibitors may circumvent this problem. Irreversible EGFR inhibitors such as HKI-272, HKI-357, and a compound developed by Wyeth Research, EKB-569, have shown some early efficacy (81,91,92). These compounds form covalent bonds with the EGFR protein at a distinct cysteine residue C773, within the kinase... 

Fry DW, Bridges AJ, Denny WA et al. Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci USA 1998 95 12022-12027. 

Irreversible inhibitors have a major advantage over their reversible counterparts in that their action is sustained after systemic clearance. However, the pharmaceutical industry usually does not make use of irreversible inhibition principles, because unspecific binding to proteins other than the target enzyme may lead to considerable toxicity. Since most of the current cancer therapies are unspecific and very toxic, the irreversible kinase inhibition principle may well be applied in this research area, provided that an improved risk/benefit ratio is observed [4e],... 

The 5 -alkylaminoadenosine (67) has been synthesised from adenosine, and found to be a potent irreversible inhibitor of S-adenosyl-L-methlonine decarboxylase. 119 A range of N-acyl derivatives (68), and corresponding N-sulphonyl compounds, have been prepzired as virzil thymidine kinase inhibitors. 120... 

Wortmannin is a fungus-derived inhibitor of PI 3-kinase. The agent binds and inhibits the enzyme covalently and irreversibly. It is very potent and considered to be highly specific (IC5o in most cells in the low nanomolar range). 

In addition to the aforementioned allenic steroids, prostaglandins, amino acids and nucleoside analogs, a number of other functionalized allenes have been employed (albeit with limited success) in enzyme inhibition (Scheme 18.56) [154-159]. Thus, the 7-vinylidenecephalosporin 164 and related allenes did not show the expected activity as inhibitors of human leukocyte elastase, but a weak inhibition of porcine pancreas elastase [156], Similarly disappointing were the immunosuppressive activity of the allenic mycophenolic acid derivative 165 [157] and the inhibition of 12-lipoxygenase by the carboxylic acid 166 [158]. In contrast, the carboxyallenyl phosphate 167 turned out to be a potent inhibitor of phosphoenolpyruvate carboxylase and pyruvate kinase [159]. Hydrolysis of this allenic phosphate probably leads to 2-oxobut-3-enoate, which then undergoes an irreversible Michael addition with suitable nucleophilic side chains of the enzyme. 

Denny WA. Irreversible inhibitors of the erbB family of protein tyrosine kinases. Pharmacol Ther 2002 93 253-61. 

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