The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase.
We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.
Malagu
Karine
K
KuDOS Pharmaceuticals Ltd, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.
Duggan
Heather
H
Menear
Keith
K
Hummersone
Marc
M
Gomez
Sylvie
S
Bailey
Christine
C
Edwards
Peter
P
Drzewiecki
Jan
J
Leroux
Frédéric
F
Quesada
Mar Jimenez
MJ
Hermann
Gesine
G
Maine
Stephanie
S
Molyneaux
Carrie-Anne
CA
Le Gall
Armelle
A
Pullen
James
J
Hickson
Ian
I
Smith
Lisa
L
Maguire
Sharon
S
Martin
Niall
N
Smith
Graeme
G
Pass
Martin
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D003959:Diamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011506:Proteins; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; C493245:CRTC2 protein, human; D003959:Diamines; D009025:Morpholines; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011743:Pyrimidines; D014157:Transcription Factors; C541932:Ku 0063794; D011494:Protein Kinases; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases