Pyrido[2,3-d]pyrimidines: discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors.
DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented.
Discovery Chemistry, Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, NJ 07110, USA.
Kevin
K
Anderson
Yi
Y
Chen
Zhi
Z
Chen
Romyr
R
Dominique
Kelli
K
Glenn
Yang
Y
He
Cheryl
C
Janson
Kin-Chun
KC
Luk
Christine
C
Lukacs
Ann
A
Polonskaia
Qi
Q
Qiao
Aruna
A
Railkar
Pamela
P
Rossman
Hongmao
H
Sun
Qing
Q
Xiang
Masha
M
Vilenchik
Peter
P
Wovkulich
Xiaolei
X
Zhang
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D000097603:Dyrk Kinases
Anti-cancer; DYRK1A; DYRK1B; Kinase-inhibitor; Pyrido[2,3-d]pyrimidine