title: Chemical and biological evaluation of dipeptidyl boronic acid proteasome inhibitors for use in prodrugs and pro-soft drugs targeting solid tumors.
abstract: Bortezomib, a dipeptidyl boronic acid and potent inhibitor of the 26S proteasome, is remarkably effective against multiple myeloma (MM) but not against solid tumors. Dose-limiting adverse effects from "on target" inhibition of the proteasome in normal cells and tissues appear to be a key obstacle. Achieving efficacy against solid tumors therefore is likely to require making the inhibitor more selective for tumor tissue over normal tissues. The simplest strategy that might provide such tissue specificity would be to employ a tumor specific protease to release an inhibitor from a larger, noninhibitory structure. However, such release would necessarily generate an inhibitor with a free N-terminal amino group, raising a key question: Can short peptide boronic acids with N-terminal amino groups have the requisite properties to serve as warheads in prodrugs? Here we show that dipeptides of boroLeu, the smallest plausible candidates for the task, can indeed be sufficiently potent, cell-penetrating, cytotoxic, and stable to degradation by cellular peptidases to serve in this capacity.
authors.affiliation: Department of Biochemistry, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, Massachusetts 02111, United States.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Milo
authors.forename: Jack H
authors.initials: JH
authors.lastname: Lai
authors.forename: Wengen
authors.initials: W
authors.lastname: Wu
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Liu
authors.forename: Hlaing
authors.initials: H
authors.lastname: Maw
authors.forename: Youhua
authors.initials: Y
authors.lastname: Li
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Jin
authors.forename: Ying
authors.initials: Y
authors.lastname: Shu
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Poplawski
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.forename: David G
authors.initials: DG
authors.lastname: Sanford
authors.forename: James L
authors.initials: JL
authors.lastname: Sudmeier
authors.forename: William W
authors.initials: WW
authors.lastname: Bachovchin
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D003500:Cyclization; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061988:Proteasome Inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004151:Dipeptides; D011355:Prodrugs; D061988:Proteasome Inhibitors; D000626:Aminopeptidases