Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and IGF-1R

Abstract

Novel 4-benzylamino benzo-anellated pyrrolo[2,3-b]pyridines have been synthesized with varied substitution patterns both at the molecular scaffold of the benzo-anellated ring and at the 4-benzylamino residue. With a structural similarity to substituted thieno[2,3-d]pyrimidines as epidermal growth factor receptor (EGFR) inhibitors, we characterized the inhibition of EGFR for our novel compounds. As receptor heterodimerization gained certain interest as mechanism of cancer cells to become resistant against novel protein kinase inhibitors, we additionally measured the inhibition of insulin-like growth factor receptor IGF-1R which is a prominent receptor for such heterodimerizations with EGFR. Structure–activity relationships are discussed for both kinase inhibitions depending on the varied substitution patterns. We discovered novel dual inhibitors of both receptor tyrosine kinases with interest for further studies to reduce inhibitor resistance developments in cancer treatment.

Pyrrole‐based EGFR inhibitors for the treatment of NCSLC: Binding modes and SARs investigations

“…Furthermore, compound 32c significantly inhibited tumor growth in a human NSCLC xenograft mouse model. Hempel et al (2017) identified a series of 4-benzylamino benzo-anellated pyrrolo[2,3-b]pyridines derivatives 33a-33c as novel dual inhibitors of receptor tyrosine kinases EGFR and IGF-1R (Figure 16). According to the anti-proliferative activity assays, the derivative 33a with the most excellent inhibitory activity against EGFR and IGF-1R kinase, with Ki values of 0.072 ± 0.017 and 0.288 ± 0.026 μM, respectively.…”

The interplay of Klotho with signaling pathway and microRNAs in cancers

“…2.1 | The role of Klotho in cancer through insulin/IGF signaling pathways Since unusual expression of peptide growth factors and their tyrosine kinases receptor enhances tumor growth and invasion and prevents apoptosis, they are important in the progression of cancer. 19 many growth factors including IGFs contribute to cancer progression and development. 20 The IGF system has a substantial character in regulating various cellular pathways, even in tumor initiation and improvement.…”

“…Since unusual expression of peptide growth factors and their tyrosine kinases receptor enhances tumor growth and invasion and prevents apoptosis, they are important in the progression of cancer . many growth factors including IGFs contribute to cancer progression and development .…”