title: Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma.
abstract: Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through the suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the antitumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing phase I clinical testing, in multiple myeloma (MM). CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G1cell cycle arrest and caspase-dependent apoptosis. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse model. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC. Given that immunomodulatory drugs (IMiDs) stabilize cereblon and facilitate Ikaros degradation in MM cells, we combined it with CPI-0610. Combination studies of CPI-0610 with IMiDs show in vitro synergism, in part due to concomitant suppression of IKZF1, IRF4 and MYC, providing a rationale for clinical testing of this drug combination in MM patients.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Siu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ramachandran
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Yee
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Eda
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Santo
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Panaroni
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Mertz
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Sims Iii
authors.affiliation: Constellation Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Cooper
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Raje
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D051740:Ikaros Transcription Factor / Q000032:analysis / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000032:analysis / Q000235:genetics; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000099218:Interferon Regulatory Factor-4; D000092468:Bromodomain Containing Proteins
chemical_list: D001552:Benzazepines; D018797:Cell Cycle Proteins; D051740:Ikaros Transcription Factor; D050835:Interferon Regulatory Factors; D007555:Isoxazoles; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C000623150:CPI-0610; C497239:IKZF1 protein, human; C489427:MYC protein, human