Aromatic interactions with phenylalanine 691 and cysteine 828: a concept for FMS-like tyrosine kinase-3 inhibition. Application to the discovery of a new class of potential antileukemia agents.
FLT3 kinase inhibitors are currently under investigation as a new treatment for acute myeloid leukemia. We report here a molecular concept invoking interactions between an aromatic ring and the side chains of Phe691 and Cys828, two residues of the ATP pocket, to obtain potent and specific inhibitors of this kinase. The hypothesis has been validated by the successful design of a new inhibitor prototype showing promising antiproliferative activity in cellular assays.
Furet
Pascal
P
Novartis Pharma AG, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland. pascal.furet@novartis.com
Bold
Guido
G
Meyer
Thomas
T
Roesel
Johannes
J
Guagnano
Vito
V
D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry*; D006801:Humans; D007951:Leukemia, Myeloid; D008958:Models, Molecular; D009154:Mutation; D010649:Phenylalanine / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics
D000970:Antineoplastic Agents; D013844:Thiazoles; D010649:Phenylalanine; D000255:Adenosine Triphosphate; D051941:fms-Like Tyrosine Kinase 3; D003545:Cysteine