Summary
Previously, we reported on the anti-tumor activities of two designed
calix[4]arene-based topomimetics (PTX008 and PTX009) of the amphipathic,
angiostatic peptide Anginex. Here, we chemically modified the hydrophobic and
hydrophilic faces of PTX008 and PTX009, and discovered new calixarene compounds
that are more potent, cytotoxic anti-tumor agents. One of them, PTX013, is
particularly effective at inhibiting the growth of several human cancer cell
lines, as well as drug resistant cancer cells. Mechanistically, PTX013 induces
cell cycle arrest in sub-G1 and G0/G1 phases of e.g. SQ20B cells, a
radio-resistant human head and neck carcinoma model. In the syngeneic B16F10
melanoma tumor mouse model, PTX013 (0.5 mg/Kg) inhibits tumor growth by about
50-fold better than parent PTX008. A preliminary pharmacodynamics study strongly
suggests that PTX013 exhibits good in vivo exposure and a relatively long
half-life. Overall, this research contributes to the discovery of novel
therapeutics as potentially useful agents against cancer in the clinic.