Use of a Pharmacophore Model for the Design of EGFR Tyrosine Kinase Inhibitors:  Isoflavones and 3-Phenyl-4(1H)-quinolones

Abstract

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.

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

“…The binding modes for ATP and erlotinib are also consistent with the existing pharmacophore model for ATP binding to kinases. 66,67,74 Significantly, a second binding mode, which has a higher affinity to the mutant kinase L834R, is revealed in our calculations. This mode still blocks the ATP binding pocket and in addition shows an additional interaction between erloitnib and the R834 residue.…”

Burkholone, A New Cytotoxic Antibiotic against IGF-I Dependent Cells from Burkholderia sp.

“…These findings suggested that 1 induced cell death not only by direct action on IGF-I-dependent pathway but also involves other action mechanism. Although, some kinase inhibitors of IGF-IR were reported [8,9], there is only one report that synthetic quinolones possessed inhibitory effects against EGFR tyrosine kinase [10]. Quinolones are reported to show antitumor effects targeting DNA related factors such as topoisomerases I and II [11ϳ15].…”

A new synthesis of novel alkenylated flavones by palladium-catalyzed cross-coupling reactions

“…They play important roles in the plant reproduction and defense and also possess a wide range of biological and pharmaceutical activities. anticonvulsive, 4 α-glucosidase inhibitor, 5 aldehyde dehydrogenase ALDH-2 inhibitor, 6 EGFR tyrosine kinase 7 and COX-2 inhibiting activity. 8 The group of 2-and 3-styrylchromones is a smaller family of chromonoids 9,10 but few representatives are known in the nature and their biological activities were also reported and reviewed.…”