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Proia DA , Smith DL , Zhang J , Jimenez JP , Sang J , Ogawa LS , Sequeira M , Acquaviva J , He S , Zhang C , Khazak V , Astsaturov I , Inoue T , Tatsuta N , Osman S , Bates RC , Chimmanamada D , Ying W
HSP90 Inhibitor-SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors
Mol Cancer Ther. 2015 Nov;14(11) :2422-32
PMID: 26271675 URL: http://www.ncbi.nlm.nih.gov/pubmed/26271675
AbstractThe clinical benefits of chemotherapy are commonly offset by insufficient drug exposures, narrow safety margins, and/or systemic toxicities. Over recent decades, a number of conjugate-based targeting approaches designed to overcome these limitations have been explored. Here, we report on an innovative strategy that utilizes HSP90 inhibitor-drug conjugates (HDC) for directed tumor targeting of chemotherapeutic agents. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to SN-38, the active metabolite of irinotecan. Mechanistic analyses in vitro established that high-affinity HSP90 binding conferred by the inhibitor backbone could be exploited for conjugate accumulation within tumor cells. In vivo modeling showed that the HSP90 inhibitor moiety was required for selective retention of STA-12-8666, and this enrichment promoted extended release of active SN-38 within the tumor compartment. Indeed, controlled intratumoral payload release by STA-12-8666 contributed to a broad therapeutic window, sustained biomarker activity, and remarkable degree of efficacy and durability of response in multiple cell line and patient-derived xenograft models. Overall, STA-12-8666 has been developed as a unique HDC agent that employs a distinct mechanism of targeted drug delivery to achieve potent and sustained antitumor effects. These findings identify STA-12-8666 as a promising new candidate for evaluation as novel anticancer therapeutic. Mol Cancer Ther; 14(11); 2422-32. (c)2015 AACR.
NotesProia, David A Smith, Donald L Zhang, Junyi Jimenez, John-Paul Sang, Jim Ogawa, Luisa Shin Sequeira, Manuel Acquaviva, Jaime He, Suqin Zhang, Chaohua Khazak, Vladimir Astsaturov, Igor Inoue, Takayo Tatsuta, Noriaki Osman, Sami Bates, Richard C Chimmanamada, Dinesh Ying, Weiwen eng 2015/08/15 06:00 Mol Cancer Ther. 2015 Nov;14(11):2422-32. doi: 10.1158/1535-7163.MCT-15-0455. Epub 2015 Aug 13.