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

Lookup NU author(s): Professor Ian HicksonORCiD

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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 × 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 <1-19 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.

Publication metadata

Author(s): Carol H, Gorlick R, Kolb EA, Morton CL, Manesh DM, Keir ST, Reynolds CP, Kang MH, Maris JM, Wozniak A, Hickson I, Lyalin D, Kurmasheva RT, Houghton PJ, Smith MA, Lock R

Publication type: Article

Publication status: Published

Journal: Pediatric Blood and Cancer

Year: 2014

Volume: 61

Issue: 2

Pages: 245-252

Print publication date: 01/02/2014

Online publication date: 04/09/2013

Acceptance date: 15/07/2013

ISSN (print): 1545-5009

ISSN (electronic): 1545-5017

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/pbc.24724

DOI: 10.1002/pbc.24724

PubMed id: 24038993

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