Abstract B101: Design and optimization of a new series of HSP70 inhibitors for use in the treatment of pancreatic cancer.

Abstract

Abstract Through a combination of structure-based design and similarity methods, we have identified a novel series of HSP70 inhibitors that are directed towards the ATPase domain. The structural core was identified through a multi-stage docking and similarity search of screening compounds available from multiple commercial sources. Upon selection of the core, a virtual library was constructed, pre-filtered, and screened in two docking packages. By combining the resulting scores with those from a docking decoy library, workflow software was used to calculate a Z-score, which has recently been shown to assist with separating actives from in-actives. ADME predicted values were also calculated for each structure in the virtual library. Filters were applied in the workflow at several points to focus on the best compounds, thirty of which were ranked and considered for synthesis. The compounds were synthesized in five steps using commercially available starting materials. At present, six compounds from the series have been synthesized and four of those were tested alone and in combination with a known proteasome inhibitor, bortezomib. The third highest ranked compound showed the most potent effect on pancreatic cancer cell death in multiple cell lines. We will report on the design, synthesis, and biological characterization of this new class of HSP70 inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B101. Citation Format: David S. Maxwell, Duoli Sun, Zhenghong Peng, Wei Qi, David McConkey, James L. Abbruzzese, William G. Bornmann. Design and optimization of a new series of HSP70 inhibitors for use in the treatment of pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B101.