Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.
The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
MethylGene Inc., 7220 Frederick-Banting, Montréal, Québec H4S 2A1, Canada.
Nancy
N
Zhou
Oscar
O
Moradei
Stephane
S
Raeppel
Silvana
S
Leit
Sylvie
S
Frechette
Frederic
F
Gaudette
Isabelle
I
Paquin
Naomy
N
Bernstein
Giliane
G
Bouchain
Arkadii
A
Vaisburg
Zhiyun
Z
Jin
Jeff
J
Gillespie
James
J
Wang
Marielle
M
Fournel
Pu T
PT
Yan
Marie-Claude
MC
Trachy-Bourget
Ann
A
Kalita
Aihua
A
Lu
Jubrail
J
Rahil
A Robert
AR
MacLeod
Zuomei
Z
Li
Jeffrey M
JM
Besterman
Daniel
D
Delorme
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011743:Pyrimidines; C523184:mocetinostat