Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2)

Abstract

A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

“…Because both the C2-C3 and C7-C8 olefins are necessary to observe the levels of toxicity seen for PL, we speculated that multivalency-the ability to interact with multiple cellular targets or a single cellular target at more than one location-might alter toxicity in this system (13)(14)(15)(16). Thus, we synthesized a structurally analogous PL"monomer," "dimer," and "trimer" using a Mitsunobu approach (Fig.…”

Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase

“…19). HKI-272 was designed using a homology model for the catalytic domain of HER-2 kinase that was built using a combination of two closely related crystal structures as templates, fibroblast growth factor receptor-1 kinase for the NH 2 -terminal lobe and hematopoietic cell kinase for the COOH-terminal lobe (18,21). The core structure of HKI-272 is similar to the structure of EKB-569 but possesses a different anilino headpiece (compare Fig.…”

“…Such groups are known to be reactive toward sulfhydryl groups. On the basis of the binding model, cysteine-805, located within the catalytic cleft of HER-2, is ideally positioned for covalent interaction with HKI-272 docked in the binding site (18). The binding model, as well as reactivity studies, suggest that the dimethylamino group present at the end of the Michael acceptor group can serve as an intramolecular catalyst for the addition of HKI-272 to the protein, which may accelerate the reaction between the bound drug and the protein.…”

“…The ErbB family has been the target of drug discovery efforts at Wyeth and has resulted in the development of EKB-569, an irreversible-binding inhibitor of EGFR, currently in clinical trials for EGFR-dependent tumors. This compound is predicted to covalently modify a cysteine residue (cysteine-773) within the ATP binding site of the kinase (18). EKB-569 shows poorer efficacy in HER-2-dependent tumor models than in EGFRdependent models (19).…”

Structure-based ensemble-QSAR model: a novel approach to the study of the EGFR tyrosine kinase and its inhibitors

“…This CW molecule bridges the interactions between THR790 and the 3-N atom of quinazoline. Wissner et al tried to replace the water molecule with a 3-cyano group, but they found that the potency was not improved by this substitution [45] . In our docking calculations, the highest TPR 1% All , TPR A 1% , and TPR C 1% values were obtained with the structures in the presence of the water molecule.…”