title: Development of a potent and selective cell penetrant Legumain inhibitor.
abstract: This Letter describes the continued SAR exploration of small molecule Legumain inhibitors with the aim of developing a potent and selective in vitro tool compound. Work continued in this Letter explores the use of alternative P2-P3 linker units and the P3 group SAR which led to the identification of 10t, a potent, selective and cellularly active Legumain inhibitor. We also demonstrate that 10t has activity in both cancer cell viability and colony formation assays.
authors.affiliation: CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Ness
authors.affiliation: CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Eddie
authors.affiliation: CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Higgins
authors.affiliation: CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Templeman
authors.affiliation: CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Zenobia
authors.initials: Z
authors.lastname: D'Costa
authors.affiliation: CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Kishore K D
authors.initials: KK
authors.lastname: Gaddale
authors.affiliation: CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Samira
authors.initials: S
authors.lastname: Bouzzaoui
authors.affiliation: Almac Discovery, Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Jordan
authors.affiliation: Almac Discovery, Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Janssen
authors.affiliation: Almac Discovery, Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Harrison
authors.affiliation: Almac Discovery, Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Burkamp
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Young
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Burden
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scott
authors.affiliation: CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Mullan
authors.affiliation: CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK. Electronic address: rich.williams@qub.ac.uk.
authors.forename: Rich
authors.initials: R
authors.lastname: Williams
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D000099240:Asparaginyl Endopeptidase
chemical_list: D003546:Cysteine Endopeptidases; D004791:Enzyme Inhibitors; D000099240:Asparaginyl Endopeptidase
keywords: Cancer; Cellular active inhibitor; Cyano warhead; Legumain