Description:
<jats:p><jats:bold>BACKGROUND AND PURPOSE</jats:bold> The use of tubulin‐binding compounds, which act in part by inhibiting tumour angiogenesis, has become an integral strategy of tumour therapy. Recently, tubulysins were identified as a novel class of natural compounds of myxobacterial origin, which inhibit tubulin polymerization. As these compounds are structurally highly complex, the search for simplified precursors [e.g. pretubulysin (Prt)] and their derivatives is mandatory to overcome supply problems hampering clinical development. We tested the anti‐angiogenic efficacy of Prt and seven of its derivatives in comparison to tubulysin A (TubA).</jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH</jats:bold> The compounds were tested in cellular angiogenesis assays (proliferation, cytotoxicity, cell cycle, migration, chemotaxis, tube formation) and <jats:italic>in vitro</jats:italic> (tubulin polymerization). The efficacy of Prt was also tested <jats:italic>in vivo</jats:italic> in a murine subcutaneous tumour model induced with HUH7 cells; tumour size and vascularization were measured.</jats:p><jats:p><jats:bold>KEY RESULTS</jats:bold> The anti‐angiogenic potency of all the compounds tested ran parallel to their inhibition of tubulin polymerization <jats:italic>in vitro</jats:italic>. Prt showed nearly the same efficacy as TubA (EC<jats:sub>50</jats:sub> in low nanomolar range in all cellular assays). Some modifications in the Prt molecule caused only a moderate drop in potency, while others resulted in a dramatic loss of action, providing initial insight into structure–activity relations. <jats:italic>In vivo</jats:italic>, Prt completely prevented tumour growth and reduced vascular density to 30%.</jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS</jats:bold> Prt, a chemically accessible precursor of some tubulysins is a highly attractive anti‐angiogenic compound both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. Even more simplified derivatives of this compound still retain high anti‐angiogenic efficacy.</jats:p>