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

  • J Adv Res. 2024 Oct:64:67-81. doi: 10.1016/j.jare.2023.11.016.
Ho Jin Han  1 ,  Aneesh Sivaraman  2 ,  Minkyoung Kim  3 ,  Kyoung Ho Min  3 ,  Mo Eun Song  3 ,  Yongseok Choi  4 ,  Won-Jun Choi  3 ,  Hyo-Kyung Han  3 ,  Junyeol Han  5 ,  Jun-Pil Jang  1 ,  In-Ja Ryoo  1 ,  Kyeong Lee  6 ,  Nak-Kyun Soung  7
Affiliations
  • 1. Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, Republic of Korea.
  • 2. College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea; School of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
  • 3. College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea.
  • 4. School of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
  • 5. Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, Republic of Korea; Department of Biomolecular Science, University of Science, and Technology, Daejeon, 34113, Republic of Korea.
  • 6. College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea; School of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea. Electronic address: [email protected].
  • 7. Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, Republic of Korea; Department of Biomolecular Science, University of Science, and Technology, Daejeon, 34113, Republic of Korea. Electronic address: [email protected].
PMID: 37977260 DOI: 10.1016/j.jare.2023.11.016
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.

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