Cancer

In vitro, cell culture and mouse studies identified a piperazine-based dual MDM2/HDAC6 inhibitor that could help treat NSCLC. Chemical synthesis and in vitro testing of conjugates consisting of analogs of the tool compound MDM2 inhibitor nutlin-3 linked to analogs of the HDAC inhibitor Zolinza vorinostat yielded a piperazine-based conjugate that bound MDM2 with a K_i of 110 nM and inhibited HDAC6 with an IC₅₀ of 17.5 nM and 10- to 70-fold selectivity for HDAC6 over HDAC1, HDAC2, HDAC3 and HDAC8. In a human NSCLC cell line, the compound inhibited growth with an IC₅₀ of 0.91 μM and increased levels of markers of apoptosis compared with nutlin-3 or Zolinza alone. In a xenograft mouse model of NSCLC, the compound decreased tumor growth compared with either control. Ongoing work includes optimization of the compound...