# Discovery of Ureido-Substituted 4-Phenylthiazole Derivatives as IGF1R Inhibitors with Potent Antiproliferative Properties

## TL;DR

Researchers developed a new compound that strongly inhibits a key protein in liver cancer and shows better effectiveness than existing drugs.

## Contribution

A novel ureido-substituted 4-phenylthiazole derivative was discovered as a potent IGF1R inhibitor with superior antiproliferative activity against HCC.

## Key findings

- Compound 27 showed stronger cytotoxicity against HepG2 cells than Sorafenib.
- Compound 27 inhibited HCC cell migration, colony formation, and induced apoptosis.
- Molecular modeling confirmed strong IGF1R binding and favorable drug-like properties for compound 27.

## Abstract

The existing kinase inhibitors for hepatocellular carcinoma (HCC) have conferred survival benefits but are hampered by adverse effects and drug resistance, necessitating the development of novel agents targeting distinct pathways. To discover potent new anti-HCC compounds, we leveraged scaffold hopping from Sorafenib and introduced morpholine/piperidine moieties to develop ureido-substituted 4-phenylthiazole analogs with optimized physicochemical properties and binding interactions. Notably, compound 27 exhibited potent cytotoxicity against HepG2 cells (IC50 = 0.62 ± 0.34 μM), significantly exceeding Sorafenib (IC50 = 1.62 ± 0.27 μM). Mechanistic investigations revealed that compound 27 potently inhibited HCC cell migration and colony formation, and it induced G2/M arrest and early-stage apoptosis. Kinase profiling revealed IGF1R as a key target, which compound 27 potently inhibited (76.84% at 10 μM). Molecular modeling substantiated compound 27’s strong binding to IGF1R via multiple hydrogen bonds. Computational predictions indicate favorable drug-like properties for compound 27. These findings provide a promising drug candidate for the treatment of HCC patients.