title: PQJS380: a novel lead compound to induce apoptosis in acute lymphoblastic leukemia cells.
abstract: Acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that are committed to the B- or the T-cell lineage. The pathogenesis of ALL is heterogeneous and may be at least in part caused by genetic alterations. Although the modern sequencing technologies make it possible to rapidly discover novel genetic and epigenetic alterations and molecular targets for therapeutic intervention for ALL, conventional chemotherapy is still the most important therapeutic approach. Relapses and high morbidity and mortality remain major challenges particularly in adult patients with ALL. Therefore, development of novel chemotherapeutic agents remains in demand for ALL patients. In the course of seeking novel agents against ALL, we screened a library of small molecules and identified that PQJS380, a S-(E)-4-([7S,10S]-4-ethyl-7-isopropyl-2,5,8,12-tetraoxo-9-oxa-3,6,13,18-tetraaza-bicycle[13,2,1] octadec-1-en-10-yl)but-3-enyl octanethioate, showed potent anti-leukemia activity. PQJS380 inhibited the proliferation with IC 50 values of 14.25 nM and 5 nM in REH and NALM-6 cells, respectively. PQJS380 had 10-fold higher molar potency than the front-line ALL drugs Ara-C and VP-16. The median IC 50 value for leukemia blast cells from 17 patients with ALL was 52 nM. PQJS380 induced G 1-phase arrest in REH cells, and S-phase in NALM-6 cells, respectively. Treatment of PQJS380 led to apoptosis in ALL cell lines (REH and NALM-6) and primary ALL cells. Our data supported that PQJS380 may be a promising lead compound for ALL treatment even though the precise targets remain to be elucidated.
authors.affiliation: Department of Pathophysiology; Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou, PR China; Key Laboratory of Tropical Disease Control; Sun Yat-sen University; Ministry of Education; Guangzhou, PR China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pathophysiology; Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou, PR China; Key Laboratory of Tropical Disease Control; Sun Yat-sen University; Ministry of Education; Guangzhou, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology; Guangzhou Institute of Biomedicine and Health; Chinese Academy of Sciences; Guangzhou Science Park; Guangzhou, PR China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics; Sun Yat-sen Memorial Hospital; Sun Yat-sen University; Guangzhou, PR China.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology; Guangzhou Institute of Biomedicine and Health; Chinese Academy of Sciences; Guangzhou Science Park; Guangzhou, PR China.
authors.forename: Yiwu
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology; Guangzhou Institute of Biomedicine and Health; Chinese Academy of Sciences; Guangzhou Science Park; Guangzhou, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Pediatrics; Sun Yat-sen Memorial Hospital; Sun Yat-sen University; Guangzhou, PR China.
authors.forename: Hongman
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Pathophysiology; Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou, PR China; Key Laboratory of Tropical Disease Control; Sun Yat-sen University; Ministry of Education; Guangzhou, PR China.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Pan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; C000591162:S-4-(4-ethyl-7-isopropyl-2,5,8,12-tetraoxo-9-oxa-3,6,13,18-tetraazabicyclo(13,2,1)octadec-1-en-10-yl)but-3-enyl octanethioate
keywords: PQJS380; acute lymphoblastic leukemia; apoptosis; chemotherapeutic agent; lead compound