title: HIF-1α suppressing small molecule, LW6, inhibits cancer cell growth by binding to calcineurin b homologous protein 1.
abstract: Hypoxia inducible factor-1 alpha (HIF-1α) plays an important role in angiogenesis and metastasis and is a promising therapeutic target for the development of anti-cancer drugs. We recently developed a new synthetic small molecule inhibitor of HIF-1α, LW6, which results in inhibition of angiogenesis. To investigate its underlying mechanism, target protein identification was conducted by reverse chemical proteomics using phage display. We identified calcineurin b homologous protein 1 (CHP1) as a target protein of LW6, which specifically binds to CHP1 in a Ca(2+) dependent manner. Covalent labeling of LW6 using photoaffinity and click chemistry demonstrated its co-localization with CHP1 in live cells. HIF-1α was decreased by CHP1 knockdown in HepG2 cells, and angiogenesis was not induced in HUVEC cells by treatment with conditioned media from CHP1 knockdown cells compared to the control. These data demonstrated that LW6 inhibited HIF-1α stability via direct binding with CHP1 resulting in suppression of angiogenesis, providing a new insight into the role of CHP1 in HIF-1α regulation. LW6 could serve as a new chemical probe to explore CHP1 function.
authors.affiliation: Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-752, Republic of Korea.
authors.forename: Beom Seok
authors.initials: BS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang 410-820, Republic of Korea.
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Engineering, SunMoon University, #100, Kalsan-ri, Tangjeong-myeon, Asan-si, Chungnam 336-708, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang 410-820, Republic of Korea.
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhattarai
authors.affiliation: Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-752, Republic of Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea. Electronic address: kwonhj@yonsei.ac.kr.
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D061505:Cell Surface Display Techniques / Q000379:methods; D057930:Click Chemistry; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy
chemical_list: D000083:Acetanilides; D020533:Angiogenesis Inhibitors; C469743:CHP1 protein, human; D002135:Calcium-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000218:Adamantane; D002118:Calcium
keywords: Angiogenesis; Calcineurin b homologous protein 1; Hypoxia-inducible factor-1α; LW6; Target identification