Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program

Abstract

Background Quisinostat (JNJ-26481585) is a second generation pyrimidyl-hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects in vivo and demonstrated improved single agent antitumoral efficacy compared to other analogs. Procedures Quisinostat was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 μM and was tested against the PPTP in vivo panels at a dose of 5 mg/kg (solid tumors) or 2.5 mg/kg (ALL models) administered intraperitoneally daily x 21. Results In vitro quisinostat demonstrated potent cytotoxic activity, with T/C% values approaching 0% for all of the cell lines at the highest concentration tested. The median relative IC50 value for the PPTP cell lines was 2.2 nM, (range <1 nM to 19 nM). quisinostat induced significant differences in EFS distribution compared to control in 21 of 33 (64%) of the evaluable solid tumor xenografts and in 4 of 8 (50%) of the evaluable ALL xenografts. An objective response was observed in 1 of 33 solid tumor xenografts while for the ALL panel, two xenografts achieved complete response (CR) or maintained CR, and a third ALL xenograft achieved stable disease. Conclusions Quisinostat demonstrated broad activity in vitro, and retarded growth in the majority of solid tumor xenografts studied. The most consistent in vivo activity signals observed were for the glioblastoma xenografts and T-cell ALL xenografts.

Discovery of protein acetylation patterns by deconvolution of peptide isomer mass spectra

“… 21 ). This drug, also known as Quisinostat, is currently in phase II clinical trial and exhibits antitumour activity in human multiple myeloma and leukaemic cells 22 23 24 25 , and recent studies have shown that JNJ-26481585 elicits global increases in acetylation of histones H3 and H4 (refs 25 , 26 ) However, owing to the inherent limitations of immunoassays, these studies did not report the specific lysine residues affected or the stoichiometries of acetylation. Our approach allowed identification of several H3 and H4 sites that increased in acetylation after JNJ-26481585 treatment.…”

p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

“…54 However, the second-generation inhibitor of Class I and II HDACs, quisinostat (JNJ-26481585), exerted profoundly increased in vivo anti-leukemic efficacy against 2 T-ALL PDXs (ALL-8 and -16) compared with 6 BCP-ALL PDXs (including ALL-2, -3, -7, -11 and -19). 55 Therefore, epigenetic silencing of p21 WAF1 may provide a biomarker for the enhanced in vivo sensitivity of T-ALL to second-generation HDAC inhibitors.…”

Biology and Treatment of Rhabdoid Tumor

“…Additional activity was noted for AZD2171 (vascular endothelial growth factor [VEGF] receptor inhibitor), ispinesib (antimitotic), SU11248 (VEGF receptor inhibitor), rapamycin (mammalian target of rapamycin inhibitor), SVV001 (oncolytic), PR-104 (alkylator), GSK923295A (centromere protein E inhibitor), MLN8237 (aurora-A-kinase inhibitor), cabozantinib (VEGF receptor/c-Met inhibitor), and RG7112 (MDM2 inhibitor). 103,108–116 Interesting additional negative results included in vitro assessment of the HDACi vorinostat (SAHA), showing high half-maximal inhibitory concentration (>2 µM) values, as well as limited activity with the HDACi JNJ-26481585 (quisinostat), 117,118 limited growth delay in vivo with topotecan, 119 and lack of in vitro or in vivo activity with CDK1/2/5/9 inhibitor SCH727965 (Dinaciclib). 120 While correlations of such preclinical testing with clinical activity in patients remains unproven, these data suggest several classes of drugs worth consideration of further clinical investigation, including VEGF multi–tyrosine kinase inhibitors as well as novel antimitotic therapies.…”