AT13387

AT13387 is a non-geldanamycin inhibitor of HSP90, it inhibited the proliferation of imatinib-sensitive (GIST882, GIST-T1) and -resistant (GIST430, GIST48) cell lines, including those resistant to the geldanamycin analogue HSP90 inhibitor, 17-AAG. AT13387 showed a median EC(50) value of 41 nM and exhibited activity consistent with a cytotoxic effect in vitro. In vivo, antitumor activity of AT13387 was showed in both the imatinib-sensitive, GIST-PSW, xenograft model and a newly characterized imatinib-resistant, GIST430, xenograft model. AT13387 has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. While AT13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models. A combination of AT13387 and imatinib treatment in the imatinib-resistant GIST430 model significantly enhanced tumor growth inhibition over either of the monotherapies.