Tubulin inhibitors development

Figure 9.11 Selective tubulin and histone deacetyiase inhibitors developed by Schreiber.

DEVELOPMENT OF TUBULIN INHIBITORS AS ANTIMITOTIC AGENTS FOR CANCER THERAPY... 

Combretastatins are a class of compounds originally derived from the African Willow tree (Combretum caffrum) and are powerful reversible inhibitors of tubulin polymerization. This class of molecules has been shown to bind to the colchicine binding site of tubulin, by the same mode of action as mentioned above (Sect. 1.2). Combretastatins consist of a ris-slilbcnc core structure. To date, there have been several compounds that have shown promise as potential anticancer drugs. However, development of these compounds as anticancer agents is limited by issues of chemical stability, bioavailibilty, toxicity, and solubility. 

Recently, Toki et al. succeeded in developing cathepsin B-activated prodrugs of combretastatin A-4 (44a, Scheme 19) and etoposide (45a, Scheme 19).60 Combre-tastatin A-4 is a promising antiangiogenic agent that inhibits the polymerization of tubulin.73 Etoposide is a clinically approved topoisomerase inhibitor that has demonstrated utility in chemotherapeutic combinations for the treatment of... 

Tubulin Human spindle Vinca alkaloids (development inhibitors)... 

Lee, KW. and Briggs, J.M. (2001) Comparative molecular field analysis (CoMFA) study of epofhilones—tubulin depolymerization inhibitors pharmacophore development using 3D QSAR methods./. Comput. Aid. Mol. Des., 15, 41—55. 

The determination of the mechanism of action of Taxol proved to be very important in the clinical development of this cytotoxic agent. Initial studies demonstrated that it was a mitotic spindle inhibitor. However, subsequent studies demonstrated that the mechanism was unique because it stabilized microtubules and prevented their depolymerization back to tubulin, an effect opposite that of other antimitotic agents as colchicine, vincristine, vinblastine, and podophyllotoxin. ... 

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