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Efficacy of a New Small-Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) in Preclinical Models of B-Cell Lymphoma and Acute Myeloid Leukemia

Montserrat Perez-Salvia, Aldaba Eneko, Vara Yosu, Fabre Myriam, Ferrer Cristina, Masdeu Carme, Zubia Aizpea, San Sebastian Eider, Otaegui Dorleta, Llinàs-Arias Pere, Rosselló-Tortella Margalida, Berdasco Maria, Setien Fernando, Moutinho Catia, Villanueva Alberto, Eva González-Barca, Josep Muncunill, Jose Tomas Navarro, Miguel Angel Piris, Cossio Fernando and Manel Esteller

Abstract

Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes. In this regard, the compound ACY-1215 (Rocilinostat), the described selective HDAC6 inhibitors, is undergoing clinical trials for the treatment of multiple myeloma. Taking into account the previous information about HDAC6 inhibitor structures, the structural differences between HDAC6 and other HDAC isoforms and also the structural information of other developed HDAC inhibitors, we have previously designed and synthesized a new potential HDAC6 selective inhibitor, QTX125 with growth inhibitory effects in mantle cell lymphoma (MCL) cell lines, mouse models and ex vivo treatment of primary samples obtained from patients with MCL. Herein, we have extended these findings to show that the newly identified HDAC6 inhibitor QTX125 is also able to inhibit the growth of preclinical models of other B-cell lymphomas such as follicular lymphoma and Burkitt's cell lymphoma, but also of acute acute myeloid leukemia. In addition beyond a-tubulin, a well known HDAC6 target, we have developed a pharmacological and proteomic screening to identify other proteins modified by HDAC6 that can contribute to the described lymphoma and leukemia phenotypes.

Disclosures Eneko: Quimatryx: Employment. Yosu: Quimatryx: Employment. Myriam: Oncomatryx: Employment. Cristina: Oncomatryx: Employment. González-Barca: Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Fernando: Quimatryx: Consultancy.

  • * Asterisk with author names denotes non-ASH members.