Abstract 1619: Hsp90 inhibitor drug conjugates (HDCs): Construct design and preliminary evaluation
Authors: Ying Weiwen , Chimmanamada Dinesh , Zhang Junyi , Przewloka Teresa , Jiang Jun , Lu Genliang , Osman Sami , Loch James , Vutukuri Dharma , Chen Shoujun , Stein Robert , Chu John , Proia David , Rao Pat , Inoue Takayo , Ogawa Luisa Shin , Singh Ritu , Tatsuta Noriaki 
Published: May 2015

Abstract
Background: Most cytotoxic agents are often broadly active but non-selective, and have the disadvantage of high toxicity due to collateral damage to normal tissues. Drugs that target specific protein drivers of cancer cell growth are more tumor selective, yet often lead to tumor resistance via point mutations in their target or activation of alternative signaling pathways. Targeted delivery strategies, such as Antibody-Drug Conjugates (ADCs), offer a solution to these limitations by delivering potent anti-cancer payloads more directly to tumors. Hsp90 is a chaperone protein required by many cancer cells to maintain the stability and function of numerous proteins that drive cancer cell growth, survival, and metastasis. Small molecule inhibitors of Hsp90 such as ganetespib, PU-H71 and 17-AAG are found to be retained in tumors with half- time up to 65 hours in mouse xenografts. These properties are believed to be due to overexpression of an active form of Hsp90 in cancer cells as compared to normal tissues, and have recently been applied for tumor imaging in patients.
Results: We have developed a small molecule drug conjugate platform technology using the unique properties of Hsp90 proteins and Hsp90 inhibitors. We have synthesized HDCs with various Hsp90 inhibitor scaffolds including resorcinol, purine, geldanamycin, etc. A cell-based client protein degradation assay is carried out to confirm the intracellular uptake and the Hsp90 binding of the conjugates. While different Hsp90 inhibitor scaffolds offer different DMPK and toxicology profiles, cellular uptake and Hsp90 binding are not greatly affected by the different chemical classes of Hsp90 inhibitors. Over 30 payloads have been conjugated with Hsp90 inhibitors so far. We have selected the payloads based on the hypothesis that HDC can improve the safety profile of a cytotoxic drug, expand the application of chemotherapeutic agents to different tumor types, combat drug resistance, and enable novel anticancer approach. Examples of payloads include topoisomerase inhibitors (camptothecin), microtubule modulators (taxanes), proteasome inhibitors (carfilzomib), CDK inhibitors (flavopiridol) and others. Unlike most other conjugate technologies, HDC does not require lengthy spacing between the anchor Hsp90 inhibitor and the payload. Linker cleavage mechanism is considered a key feature in the HDC design. We have been able to incorporate several linkers such as disulfide, hydrazone, peptide, carbamate, carboxylate, etc. into our HDC designs.
Conclusion: In this HDC platform, we provide a method which can be applied to many well-studied mechanisms for modulating cancer pathways and stopping tumor cell growth. We have created a promising platform technology which can result in many anticancer agents in the near future.
Citation Format: Weiwen Ying, Dinesh Chimmanamada, Junyi Zhang, Teresa Przewloka, Jun Jiang, Genliang Lu, Sami Osman, James Loch, Dharma Vutukuri, Shoujun Chen, Robert Stein, John Chu, David Proia, Pat Rao, Takayo Inoue, Luisa Shin Ogawa, Ritu Singh, Noriaki Tatsuta. Hsp90 inhibitor drug conjugates (HDCs): Construct design and preliminary evaluation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1619. doi:10.1158/1538-7445.AM2014-1619