Aneesh Sivaraman (동국대학교 약학대학)

한빛사논문

조회309

동국대학교 약학대학

J. Adv. Res., Nov 15 2023, S2090-1232(23)00353-3 | https://doi.org/10.1016/j.jare.2023.11.016 HIF-1α inhibition by MO-2097, a novel chiral-free benzofuran targeting hnRNPA2B1

Ho Jin Han ^a,1, Aneesh Sivaraman ^b,c,1, Minkyoung Kim ^b, Kyoung Ho Min ^b, Mo Eun Song ^b, Yongseok Choi ^c, Won-Jun Choi ^b, Hyo-Kyung Han^b, Junyeol Han ^a,d, Jun-Pil Jang ^a, In-Ja Ryoo ^a, Kyeong Lee ^b,c, Nak-Kyun Soung ^a,d

^aChemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, Republic of Korea

^bCollege of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea

^cSchool of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea

^dDepartment of Biomolecular Science, University of Science, and Technology, Daejeon, 34113, Republic of Korea

¹These authors contributed equally to this work.

Corresponding authors : Kyeong Lee, Nak-Kyun Soung

Abstract

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. This study aimed to develop novel HIF-1 inhibitors for cancer chemotherapy by harnessing the potential of the natural products moracins-O and P. 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. 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. MO-2097 represents a promising new generation of chemotherapeutic agents targeting HIF-1α inhibition via hnRNPA2B1, requiring further investigation.

논문정보

형식Research article
게재일2023년 11월 (BRIC 등록일 2023-11-20)
연구진국내 연구진
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