title: Synthesis and Evaluation of a Novel Deguelin Derivative, L80, which Disrupts ATP Binding to the C-terminal Domain of Heat Shock Protein 90.
abstract: The clinical benefit of current anticancer regimens for lung cancer therapy is still limited due to moderate efficacy, drug resistance, and recurrence. Therefore, the development of effective anticancer drugs for first-line therapy and for optimal second-line treatment is necessary. Because the 90-kDa molecular chaperone heat shock protein (Hsp90) contributes to the maturation of numerous mutated or overexpressed oncogenic proteins, targeting Hsp90 may offer an effective anticancer therapy. Here, we investigated antitumor activities and toxicity of a novel deguelin-derived C-terminal Hsp90 inhibitor, designated L80. L80 displayed significant inhibitory effects on the viability, colony formation, angiogenesis-stimulating activity, migration, and invasion of a panel of non-small cell lung cancer cell lines and their sublines with acquired resistance to paclitaxel with minimal toxicity to normal lung epithelial cells, hippocampal cells, vascular endothelial cells, and ocular cells. Biochemical analyses and molecular docking simulation revealed that L80 disrupted Hsp90 function by binding to the C-terminal ATP-binding pocket of Hsp90, leading to the disruption of the interaction between hypoxia-inducible factor (HIF)-1α and Hsp90, downregulation of HIF-1α and its target genes, including vascular endothelial growth factor (VEGF) and insulin-like growth factor 2 (IGF2), and decreased the expression of various Hsp90 client proteins. Consistent with these in vitro findings, L80 exhibited significant antitumor and antiangiogenic activities in H1299 xenograft tumors. These results suggest that L80 represents a novel C-terminal Hsp90 inhibitor with effective anticancer activities with minimal toxicities.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Su-Chan
authors.initials: SC
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Min
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Hoon
authors.initials: H
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Ho Shin
authors.initials: HS
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Kyong-Cheol
authors.initials: KC
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: So-Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Myeong A
authors.initials: MA
authors.lastname: Seong
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Hong
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Hee
authors.initials: H
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.).
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea (S.-C.L., H.-Y.M., H.C., H.S.K., K.-C.K., M.A.S., J.H.S., Y.-G.S., K.-W.K., J.L., H.-Y.L.); School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea (S.-J.P., H.-J.P.); and Medifron-DBT, Ansan, Republic of Korea (H.-S.H., H.K., M.-Y.L.) hylee135@snu.ac.kr.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000494:pharmacology; D001578:Benzopyrans / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D011804:Quinolines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D012402:Rotenone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000601052:(6,7-dimethoxyquinolin-4-yl)(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl acetate; D000970:Antineoplastic Agents; D001578:Benzopyrans; D018841:HSP90 Heat-Shock Proteins; D011804:Quinolines; D012402:Rotenone; C107676:deguelin