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. 2024 Nov 15:113:129971.
doi: 10.1016/j.bmcl.2024.129971. Epub 2024 Sep 19.

Discovery of novel, orally bioavailable phenylacetamide derivatives as multikinase inhibitors and in vivo efficacy study in hepatocellular carcinoma animal models

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Discovery of novel, orally bioavailable phenylacetamide derivatives as multikinase inhibitors and in vivo efficacy study in hepatocellular carcinoma animal models

Debasis Das et al. Bioorg Med Chem Lett. .

Abstract

Hepatocellular carcinoma (HCC) is considered as one of the leading causes of death in liver disease patients. Several signal transduction pathways are involved in HCC pathogenesis. Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. Here, a novel series of phenylacetamide derivatives were designed, synthesized and evaluated as multikinase inhibitors. Several compounds showed nanomolar IC50 values against FLT1, FLT3, FLT4, KDR, PDGFRα, PDGFRβ. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compound 12 and compound 14 were selected for in vivo efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib.

Keywords: HCC; Hep3B animal model; Hepatocellular carcinoma; Inhibitor; Multikinase; Xenografts.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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