HIF-1α inhibition by MO-2097, a novel chiral-free benzofuran targeting hnRNPA2B1

Ho Jin Han, Aneesh Sivaraman, Minkyoung Kim, Kyoung Ho Min, Mo Eun Song, Yongseok Choi, Won Jun Choi, Hyo Kyung Han, Junyeol Han, Jun Pil Jang, In Ja Ryoo, Kyeong Lee, Nak Kyun Soung

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Introduction: Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator mediating adaptive responses to hypoxia. It is up-regulated in the tumor microenvironment and recognized as an effective anticancer drug target. Previously, we discovered that the natural compound moracin-O and its synthetic derivative MO-460 inhibited HIF-1α via hnRNPA2B1. Objectives: This study aimed to develop novel HIF-1 inhibitors for cancer chemotherapy by harnessing the potential of the natural products moracins-O and P. Methods: In an ongoing search for novel HIF-1 inhibitors, a series of nature-inspired benzofurans with modifications on the chiral rings of moracins-O and P were synthesized. They showed improved chemical tractability and were evaluated for their inhibitory activity on HIF-1α accumulation under hypoxic conditions in HeLa CCL2 cells. The most potent derivative's chemical-based toxicities, binding affinities, and in vivo anti-tumorigenic effects were evaluated. Further, we examined whether our compound, MO-2097, exhibited anticancer effects in three-dimensional cultured organoids. Results: Herein, we identified a novel synthetic chiral-free compound, MO-2097, with reduced structural complexity and increased efficiency. MO-2097 exhibited inhibitory effects on hypoxia-induced HIF-1α accumulation in HeLa CCL2 cells via inhibition of hnRNPA2B1 protein, whose binding affinities were confirmed by isothermal titration calorimetry analysis. In addition, MO-2097 demonstrated in vivo efficacy and biocompatibility in a BALB/c mice xenograft model. The immunohistochemistry staining of MO-2097-treated tissues showed decreased expression of HIF-1α and increased levels of apoptosis marker cleaved caspase 3, confirming in vivo efficacy. Furthermore, we confirmed that MO-2097 works effectively in cancer patient-based organoid models. Conclusion: MO-2097 represents a promising new generation of chemotherapeutic agents targeting HIF-1α inhibition via hnRNPA2B1, requiring further investigation.

Original languageEnglish
Pages (from-to)67-81
Number of pages15
JournalJournal of Advanced Research
Volume64
DOIs
StatePublished - Oct 2024

Keywords

  • HIF-1α inhibition
  • Nature-inspired chiral-free benzofuran
  • Patient-derived cancer organoid
  • RNA-binding protein
  • hnRNPA2B1

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