Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington's disease.
Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.
Evotec (UK) Ltd., 114 Milton Park, Abingdon, OX14 4SA, UK.
Michael E
ME
Prime
Ole A
OA
Andersen
John J
JJ
Barker
Mark A
MA
Brooks
Robert K Y
RK
Cheng
Ian
I
Toogood-Johnson
Stephen M
SM
Courtney
Frederick A
FA
Brookfield
Christopher J
CJ
Yarnold
Richard W
RW
Marston
Peter D
PD
Johnson
Siw F
SF
Johnsen
Jordan J
JJ
Palfrey
Darshan
D
Vaidya
Sayeh
S
Erfan
Osamu
O
Ichihara
Brunella
B
Felicetti
Shilpa
S
Palan
Anna
A
Pedret-Dunn
Sabine
S
Schaertl
Ina
I
Sternberger
Andreas
A
Ebneth
Andreas
A
Scheel
Dirk
D
Winkler
Leticia
L
Toledo-Sherman
Maria
M
Beconi
Douglas
D
Macdonald
Ignacio
I
Muñoz-Sanjuan
Celia
C
Dominguez
John
J
Wityak
D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
D000178:Acrylamides; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; C000717608:TGM2 protein, human; C000717609:Tgm2 protein, rat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins