Kinase, kinases irreversible inhibitors

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

Fry DW. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy progression from reversible to irreversible inhibitors. Pharmacol Ther 1999 82 207-218. 

In the course of studying the mechanism of action of creatine kinase from rabbit skeletal muscle (M.M isoenzyme), Kenyon and coworkers (4,90) have been involved in the design of specific irreversible inhibitors that are active-site-directed (affinity labels). Creatine kinase catalyzes the reversible transfer of a phosphoryl group ( the elements of "POi") from ATP to creatine, as shown in the following reaction ... 

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... 

Rabindran SK, Discafani CM, Rosljord EC et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 2004 64 3958-3965. 

Wissner A, Overbeek E, Reich MF et al. Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (ElER-2). JMed Chem 2003 46 49-63. 

Singh J, Dobrusin EM, Fry DW et al. Structure-based design of a potent, selective, and irreversible inhibitor of the catalytic domain of the erbB receptor subfamily of protein tyrosine kinases. J Med Chem 1997 40 1130-1135. 

Iressa (gefitinib, 2) is a reversible inhibitor, thus mechanistically it is possible to excert less toxicity in comparison to similar irreversible inhibitors, which bond to the protein covalently. Gefitinib (2) is also quite selective. It is at least 100-fold selective against other tyrosine kinases such as erbB-2, KDR, c-flt or serine/threonine kinases such as PKC, MEK-1, and ERK-2. 

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 first example of an irreversible inhibitor is the natural product Wortmannin, which was isolated from Penicillium wortmannii [30], Wortmannin effectively inhibits PI3K at low nanomolar concentration and was shown to be specific across a large panel of kinases [31]. Covalent attachment to PI3K occurs after attack by Lys-883, which is essential for phosphate transfer (see Section 7.2), at the furan ring of Wortmannin [32], Attack at this ring specifically occurs within the catalytic site of the PI3K kinase and is unaffected by nucleophiles in aqueous solution. 

The 6-acrylamido-4-anilinoquinazolines constitute another class of irreversible inhibitor targeted at the EG Fr tyrosine kinase. This type of inhibitor has been derived from the very potent (6 pM) and selective 4-anilinoquinazolines, e.g., PD-0153035 [4e], A detailed description of the binding mode of the 4-anilinoquinazolines is given in Section 7.4.1. The Michael acceptor at the 6-position of the 4-anilino-... 

Fig. 5.6 Examples of novel small molecule and peptide radiotracers for in vivo pharmacodynamic imaging, (a) f C]ML03, an irreversible inhibitor of EGFR tyrosine kinase and potential PET marker for the receptor (b) f F]SAV03, an MMP-2 inhibi-...

Fry, D.W. Site-directed irreversible inhibitors of the erbB family of receptor tyrosine kinases as novel chemotherapeutic agents for cancer. Anticancer Drug Des., 15, 3-16 (2000)... 

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