Lead identification to generate 3-cyanoquinoline inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment

Abstract

Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. Inhibitors of this receptor are believed to provide a new target in cancer therapy. We previously reported an isoquinolinedione series of IGF-1R inhibitors. Now we have identified a series of 3-cyanoquinoline compounds that are low nanomolar inhibitors of IGF-1R. The strategies, synthesis, and SAR behind the cyanoquinoline scaffold will be discussed.

Serine Phosphorylation of the Insulin-like Growth Factor I (IGF-1) Receptor C-terminal Tail Restrains Kinase Activity and Cell Growth

“…To do this, we examined crystal structures of the IGF-1R kinase that, although C-terminally truncated after amino acid 1256, encompass the SFYYS motif. These include crystal structures with the kinase A-loop in various states of phosphorylation (from unphosphorylated to fully phosphorylated) and variously complexed with ATP mimetics, inhibitors, and phospho-acceptor peptide substrates (7,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In these structures, the unphosphorylated SFYYS motif universally adopts a conformation tightly packed against helices ␣I and ␣E of the kinase C-lobe (Fig.…”

“…We also used the available crystal structures that, although truncated below amino acid 1256, encompass the SFYYS motif (7,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and enabled us to explore the structural basis for this motif in regulating IGF-1R activity. Our findings indicate that a direct regulatory interaction of the C terminus with the kinase domain can be controlled by phosphorylation of Ser-1248.…”

Molecular design and synthesis of certain new quinoline derivatives having potential anticancer activity

“…Some of the anilinoquinolines (I) [29] act as anti-tumour agents by inhibiting CSF-1 kinase while few 3-cyanoquinolines (II) [30] developed as inhibitors of insulin like growth factor receptors (IGF-1R). A few 4-anilinoquinolines (III) [31] have been found to be TK inhibitors.…”

“…Molecular field analysis of 4-anilinoquinazoline, 4-anilinoquinoline-3-carbonitrile and 4-anilinoquinoline-3-carboxamide [cyan: quinazoline as a reference; pink: 3-cyanoquinoline (similarity = 0.823) and orange: quinoline-3-carboxamide (similarity = 0.868)]. The literature compounds used as a training set in the pharmacophore building with their IC 50 values[29,30,32,33,35,36,[43][44][45]. a) The common features pharmacophore generated from training set; two hydrophobic centers (1, 2; cyan color), one HBD (magenta color) and two HBA (green color).…”

Discovery and SAR of Thiazolidine-2,4-dione Analogues as Insulin-like Growth Factor-1 Receptor (IGF-1R) Inhibitors via Hierarchical Virtual Screening

“…5 Tremendous efforts have been made toward finding small molecules as IGF-1R ATP-competitive inhibitors. The selected structures of four potent inhibitors of IGF-1R kinase at discovery or preclinical stage are presented in Figure S1, which include benzimidazoles (1, BMS), 6 isoquinolinediones (2, Wyeth), 7 3-cyanoquinolines (3, Wyeth), 8 and pyrazolopyrimidines (4, Abbott). 9 Several cocrystal structures of IGF-1R with the inhibitors mentioned above have been determined and the ATP-binding site is confirmed as the inhibitors' binding site, which provides us crucial structural information for screening and design of novel IGF-1R inhibitors.…”