PQJS']JS380 A novel lead compound to induce apoptosis in acute lymphoblastic leukemia cells

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 IC50 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 IC50 value for leukemia blast cells from 14 patients with ALL was 40 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.