Convincing biological data indicate an important role for grp94, the endoplasmic reticulum HSP90 paralog, in the progression and maintenance of a malignant phenotype. The overall objective of this PPG is to advance the fundamental understanding of grp94 with the ultimate goal of developing rational grp94-based molecular therapeutics against cancer. Thus, the three integrated Projects collectively aim to unveil the mechanisms behind the tumor roles of grp94 and also provide a structural and biochemical understanding of how grp94 influences these functions. These efforts ultimately will result in an understanding of how best to introduce grp94 inhibitors for the treatment of cancers. To aid these efforts, Project 2 will continue to develop chemical tools that will facilitate the mechanistic studies conducted throughout the PPG. These tools are selective, cell permeable small molecule ligands that can be used to elucidate tumor-cell grp94 functions in a time- and concentration-specific manner. These tools also are drug-like grp94 inhibitors that will enable in vivo investigation of the potential of grp94 as a target in cancers. The overarching objective of the Medicinal Chemistry (Core 2) is to provide these tools in the amount and quality required by the three Projects in a time- and cost-effective manner. To catalyze and facilitate the proposed PPG efforts, Core 2 will generate large quantities of these tools to make sufficient amounts of grp94-related materials available to facilitate proposed the studies. Core 2 will perform quality control on the synthesized materials (i.e., verify selectivity, proper structure and purity), formulate the agent for the proposed use (e.g., make the appropriate formulation for in vivo use), and ship the materials to the PPG investigator with instructions for handling and storage. Specifically, Core 2 will: 1. Conduct scale-up syntheses and compound characterization for requested grp94 inhibitors and control compounds (e.g., the pan-Hsp90 inhibitor PU-H71) required by the four Projects. 2. Perform formulation and stability studies on compounds with the goal of delivering `ready-to-use' tools for in vivo studies (e.g., preparation of agents for in vivo studies, storage and handling of inhibitor stocks). 3. Perform specificity testing of key compounds to probe their selectivity for grp94 and inquire into potential off-target related toxicities (e.g., screening in ?off-target? and ?tox? panels such as Caliper LifeSciences' General Side Effect PROFILE II (GEN SEP II) and Ambit's kinase screens). 4. Conduct in vivo DMPK studies (i.e., PK, tumor PD, preliminary tox and efficacy) on select compounds resulting from Project 2 to provide PPG investigators with information on proper in vivo use (e.g., dose and schedule for in vivo studies, route of administration). 5. Provide upon request grp94 chemical tools (e.g., grp94 inhibitors for in vitro and in vivo studies, derivatized grp94 ligands such as solid-support immobilized inhibitors) and control compounds (i.e., pan-HSP90 inhibitor PU-H71) for the three Projects. Significance. Core 2 is the interfacing entity of all the projects. It has extensive resources and expertise and is positioned to provide unique resources for a judicious and timely completion of the proposed PPG efforts.
The goal of the Medicinal Chemistry Core (Core 2) is to provide the chemical tools needed by the three PPG projects for investigation of grp94 in cancer. All three projects will utilize grp94-selective inhibitors to address various aspects of grp94 biology in cancer with an ultimate objective of developing novel grp94-based cancer therapeutics. The collective results of these integrated investigations should lay the groundwork for more effective treatments for a number of human cancers, such as breast, colon, lung and prostate cancers and multiple myeloma.
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