P3 SAR exploration of biphenyl carbamate based Legumain inhibitors.
This Letter describes the further development and SAR exploration of a novel series of Legumain inhibitors. Based upon a previously identified Legumain inhibitor from our group, we explored the SAR of the carbamate phenyl ring system to probe the P3 pocket of the enzyme. This led to the identification of a sub-nanomolar inhibitor of Legumain.
CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
Catherine
C
Higgins
CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
Samira
S
Bouazzaoui
CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
Kishore
K
Gaddale
CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
Zenobia
Z
D'Costa
CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
Amy
A
Templeman
Almac Discovery, Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, UK.
Martin
M
O'Rourke
School of Pharmacy, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
Andrew
A
Young
CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK; School of Pharmacy, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
Christopher
C
Scott
CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK; Almac Discovery, Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, UK.
Tim
T
Harrison
CCRCB Drug Discovery Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Rd., Belfast BT9 7BL, UK.
Paul
P
Mullan
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.
Rich
R
Williams
D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D000099240:Asparaginyl Endopeptidase
D001713:Biphenyl Compounds; D002219:Carbamates; D003546:Cysteine Endopeptidases; D004791:Enzyme Inhibitors; D000099240:Asparaginyl Endopeptidase; C010574:biphenyl
Cancer; Cyano warhead; Legumain; Protease inhibitor