Multi-kinase inhibitors

In the search for an optimal lead compound, not only activity on the desired target but also activity on other targets should be considered. Sometimes, multi-protein-targeting is desired, e.g., for multi-kinase inhibitors in the oncology field. However, also activity on side effect-related targets - so-called antitargets -is to be investigated. Compounds with no or very low affinity to proteins related to cardiovascular, cytotoxic, or metabolic effects are more likely to pass... 

Ozvegy-Laczka C, Elegedus T, Varady G et al. High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multi drug transporter. Mol Pharmacol 2004 65 1485-1495. 

Kamath AV et al (2008) Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825) a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Cancer Chemother Pharmacol 61 365-376... 

Baratte S et al (2004) Quantitation of SU1 1248, an oral multi-target tyrosine kinase inhibitor, and its metabolite in monkey tissues by liquid chromatograph with tandem mass spectrometry following semi-automated liquid-liquid extraction. J Chromatogr A 1024 87-94... 

Systems Biology Insights into Wrapping-Directed Design of Multi-target Kinase Inhibitors... 

The first kinase inhibitor to be developed for clinical use was imatinib 42, first marketed in 2001 for chronic myelogenous leukemia (CML). The clinical effectiveness of imatinib for the treatment of CML is now thought to be due to its multi-kinase activity, inhibiting PDGFR and c-KIT, in addition to its well known activity as a Bcr-Abl kinase inhibitor. Resistance to imatinib can become a problem due to mutations in the Abl gene. Dual Src/Abl inhibitors are currently of interest for the treatment of CML... 

Fig. 2 Structure of a multi-acting HDAC and kinase inhibitor...

---