Novel Imatinib Derivatives with Altered Specificity between Bcr–Abl and FMS, KIT, and PDGF Receptors

Abstract

Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr-Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N-methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity.

Liquid crystal-related compound-induced cell growth suppression and apoptosis in the chronic myelogenous leukemia K562 cell line

“…Recently, the development of a new class of drugs such as molecular targeted agents has shown remarkable results [6]. Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease characterized by the Philadelphia-chromosome translocation that encodes a chimeric protein BCR-ABL tyrosine kinase.…”

Transgenic mouse models of hormonal mammary carcinogenesis: Advantages and limitations

“…However, such drugs also have nonspecific actions and target other kinases and receptor tyrosine kinases similar to c-fms. More recent compounds with high specificity against c-fms have been developed [8,68]. The MMTV-PYMT and CSF-1 transgenic models may therefore be used as preclinical models to investigate the efficacy of these drugs.…”

Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives

“…1), a hybrid/variant of imatinib having the active pharmacophore PPAP (Fig. 1) [26] conserved in its structure; the drug is efficacious in imatinib resistant cases [27]. On the basis of above and considering the literature reports discussing Abl-imatinib structural interactions [16,[26][27][28][29][30][31][32], we decided to conjugate the scaffolds based on 2-pyridone [21,33,34], benzopyran-2-one [35], benzopyran-4-one [22,36], indole acetic acid, iso-nicotinic acid, hippuric acid, piperic acid, 2-oxoquinolinacetic acid, 3-oxobenzooxazinacetic acid [37], and trimethoxyphenyl acrylic acid [38], with PPAP moiety to form the amide/cyclic amide derivatives.…”