Identification and optimisation of novel and selective small molecular weight kinase inhibitors of mTOR.
A pharmacophore mapping approach, derived from previous experience of PIKK family enzymes, was used to identify a hit series of selective inhibitors of the mammalian target of rapamycin (mTOR). Subsequent refinement of the SAR around this hit series based on a tri-substituted triazine scaffold has led to the discovery of potent and selective inhibitors of mTOR.
Menear
Keith A
KA
KuDOS Pharmaceuticals Ltd, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE, UK.
Gomez
Sylvie
S
Malagu
Karine
K
Bailey
Christine
C
Blackburn
Kristel
K
Cockcroft
Xiao-Ling
XL
Ewen
Sally
S
Fundo
Alexandra
A
Le Gall
Armelle
A
Hermann
Gesine
G
Sebastian
Luisa
L
Sunose
Mihiro
M
Presnot
Thomas
T
Torode
Eleanor
E
Hickson
Ian
I
Martin
Niall M B
NM
Smith
Graeme C M
GC
Pike
Kurt G
KG
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C546842:MTOR protein, human