title: Design, synthesis, and biological evaluation of bone-targeted proteasome inhibitors for multiple myeloma.
abstract: Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Standard chemotherapeutic agents have not been effective at significantly prolonging the survival of MM patients and these agents are typically associated with often severe, dose-limiting side effects. There is great need for methods to target the delivery of novel, effective cytotoxic agents specifically to bone, where myeloma cells reside. We have synthesized and evaluated the effects of the bone-targeted proteasome inhibitors PS-341-BP-1, PS-341-BP-2 and MG-262-BP on cell proliferation using the mouse 5TGM1 and human RPMI 8226 cell lines in vitro. The compounds exhibit strong cytotoxicity on MM cell lines and reduce the number of viable cells in a dose dependent manner.
authors.affiliation: University of Texas Health Science Center at San Antonio, Biochemistry Department, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States; University of Texas Health Science Center at San Antonio, Cellular and Structural Biology Department, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States. Electronic address: agyinj@uthscsa.edu.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Agyin
authors.forename: Bindu
authors.initials: B
authors.lastname: Santhamma
authors.forename: Sudipa S
authors.initials: SS
authors.lastname: Roy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D001897:Boronic Acids; D004164:Diphosphonates; D061988:Proteasome Inhibitors
keywords: Bisphosphonate conjugate; Bone-targeted; Boronic acid; Multiple myeloma; Proteasome inhibitor