title: Design, syntheses, and evaluation of Taspase1 inhibitors.
abstract: Taspase1 is a threonine protease responsible for cleaving MLL (Mixed-Lineage Leukemia) to achieve proper HOX gene expression. Subsequent studies identified additional Taspase1 substrates including Transcription Factor IIA (TFIIA) and Drosophila HCF. Taspase1 is essential for cell proliferation and is overexpressed in many cancer cell lines. Currently no small molecule inhibitors of this enzyme have been described. Here, we report the synthesis and evaluation of vinyl sulfone, vinyl ketone, epoxy ketone, and boronic acid inhibitors designed based on the preferred Taspase1 cleavage site (Ac-Ile-Ser-Gln-Leu-Asp). Specifically, we evaluated compounds in which the reactive warhead is positioned in place of the P1 aspartic acid side chain as well as at the C-terminus of the peptide. Interestingly, both classes of inhibitors were effective and vinyl ketones and vinyl sulfones showed the greatest potency for the target protease. These results suggest that Taspase1 has unique substrate recognition properties that could potentially be exploited in the design of potent and selective inhibitors of this enzyme.
authors.affiliation: Department of Pathology, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Jeong Tae
authors.initials: JT
authors.lastname: Lee
authors.forename: David Y
authors.initials: DY
authors.lastname: Chen
authors.forename: Zhimou
authors.initials: Z
authors.lastname: Yang
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Ramos
authors.forename: James J-D
authors.initials: JJ
authors.lastname: Hsieh
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000595:Amino Acid Sequence; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; D007659:Ketones; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013450:Sulfones; D010450:Endopeptidases; C480823:taspase1, human