One of the major challenges in cancer treatment is to selectively deliver oncology drugs directly to tumors, and thus spare normal tissues. One successful approach to meet this challenge is demonstrated by the development of Antibody Drug Conjugates (ADCs). It has been shown in human cancer patients and mouse xenografts that heat shock protein 90 (Hsp90) is overexpressed in tumors, and inhibitors of Hsp90 are preferentially retained in tumor tissue in contrast to their rapid clearance from normal tissues. We have developed a small-molecule drug conjugate platform technology using these unique properties of Hsp90 proteins and Hsp90 inhibitors. Hsp90-Inhibitor Drug Conjugates (HDCs) offer many of the advantages of antibody-driven targeted delivery with potentially broader applicability. To date, we have conjugated over 40 payloads representing various oncology drug categories to Hsp90 inhibitors. Conjugates with payloads like SN-38 and docetaxel have been advanced into preclinical studies and have been shown to prolong intratumoral drug exposure in mouse xenografts, reduce on-target adverse effects, and confer superior efficacy in a variety of tumor types.In HDCs, we have created a promising platform technology which will result in many novel anticancer agents in the near future.

Hsp90 inhibitor drug conjugates (HDCs): Proof of concept in preclinical studies

248th National Meeting (2014)

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