The primary source from which APIs were selected was the FDA publication Approved Drug Products with 1028385-32-1 cost Therapeutic Equivalence and Evaluations colloquially known as the Orange Book, which identifies drug products approved on the basis of safety and effectiveness by the FDA under the Federal Food, Drug, and Cosmetic Act. Our target library included 1262 APIs, 250 of which were under patent at the time of the creation of the library. Although Safe Harbor provisions provide broad immunity from patent Daucosterol infringement for preclinical research and experimentation including drug screening, we gathered on-patent compounds under Material Transfer Agreements with the approval of patent holders. We were able to obtain a total of 1012 APIs for use in the screens. The paradigm of cancer treatment has been dramatically changed by the introduction of small molecular compounds that target the Achilles�� heel���� of cancer cells. The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Cancer cells are very sensitive to proteotoxic stress because of intracellular protein overload due to rapid cell cycling and apoptosis inhibition. This feature makes proteasome inhibition a unique and effective way to kill cancer cells that can tolerate conventional therapies. Bortezomib is the first proteasome inhibitor approved for clinical application, which preferentially targets ?1 and ?5 subunits of the proteasome. This drug is particularly effective for multiple myeloma, because it accelerates the unfolded protein response via down-regulation of histone deacetylases and targets cell adhesion-mediated drug resistance via down-regulation of very late antigen-4. Accordingly, bortezomib is now indispensable for the treatment of MM in combination with other anti-cancer drugs including alkylating agents, corticosteroids and HDAC inhibitors. Although bortezomib therapy is a major advance in clinical oncology, there are at least three major problems to be resolved as soon as possible. First, bortezomib has several possible off-target toxicities. Second, the development of intrinsic and acquired resis
