Use of a pharmacophore model for the design of EGFR tyrosine kinase inhibitors: isoflavones and 3-phenyl-4(1H)-quinolones.
Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the Hck tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in 1, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6, 7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-dihydroxyisoflavone (6) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of 11 did not further improve enzyme inhibitory activity but led to derivatives with cellular activity in the lower micromolar range.
Traxler
P
P
NOVARTIS Pharmaceuticals, Therapeutic Area Oncology, NOVARTIS Limited, CH-4002 Basel, Switzerland.
Green
J
J
Mett
H
H
Séquin
U
U
Furet
P
P
D000818:Animals; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D019833:Genistein / Q000378:metabolism; D007529:Isoflavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C118217:3'-chloro-5,7-dihydroxyisoflavone; D004791:Enzyme Inhibitors; D007529:Isoflavones; D015363:Quinolones; D019833:Genistein; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases