title: Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice.
abstract: Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic transcriptional regulators required for efficient expression of growth promoting, cell cycle progression and antiapoptotic genes. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET-histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation. JQ1 is a small molecule that blocks BET interaction with histones. It has been shown to decrease proliferation of patient-derived multiple myeloma in vitro and to decrease tumor burden in vivo in xenograft mouse models. While targeting BET appears to be a viable and efficacious approach, the nonclinical safety profile of BET inhibition remains to be well-defined. We report that mice dosed with JQ1 at efficacious exposures demonstrate dose-dependent decreases in their lymphoid and immune cell compartments. At higher doses, JQ1 was not tolerated and due to induction of significant body weight loss led to early euthanasia. Flow cytometry analysis of lymphoid tissues showed a decrease in both B- and T-lymphocytes with a concomitant decrease in peripheral white blood cells that was confirmed by hematology. Further investigation with the inactive enantiomer of JQ1 showed that these in vivo effects were on-target mediated and not elicited through secondary pharmacology due to chemical structure.
authors.affiliation: Department of Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address: lee.dong@gene.com.
authors.forename: Dong U
authors.initials: DU
authors.lastname: Lee
authors.affiliation: Department of Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Katavolos
authors.affiliation: Department of Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Gopinath
authors.initials: G
authors.lastname: Palanisamy
authors.affiliation: Department of Research Immunology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Arna
authors.initials: A
authors.lastname: Katewa
authors.affiliation: Department of Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Charly
authors.initials: C
authors.lastname: Sioson
authors.affiliation: Department of Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Corpuz
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: DeMent
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Edna
authors.initials: E
authors.lastname: Choo
authors.affiliation: Department of Research Immunology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.affiliation: Department of Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Diaz
authors.affiliation: Department of Safety Assessment, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Dimitry M
authors.initials: DM
authors.lastname: Danilenko
mesh_terms: D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057890:Epigenomics; D007107:Immune System / Q000187:drug effects* / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012156:Reticulocytes / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D014230:Triazoles; D017346:Protein Serine-Threonine Kinases
keywords: Bromodomain; Epigenetics; Immunology; Lymphocytes; Toxicology