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Molecular targets for therapy

Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma

Leukemia volume 31, pages 1760–1769 (2017)Cite this article

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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 G1 cell 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.

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Acknowledgements

We thank members of Dr David Scadden’s laboratory: David Sykes, Youmna Kfoury, Francois Mercier, Dongjun Lee, Ninib Baryawno, Nicolas Sévère, Karin Gustafsson and Demetrios Kalaitzidis at Massachusetts General Hospital for helpful discussion. This work is supported by the Multiple Myeloma Research Fund at MGH. Constellation Pharmaceuticals, Inc., provided the CPI-0610 compound.

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Authors and Affiliations

  1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    K T Siu, J Ramachandran, A J Yee, H Eda, L Santo, C Panaroni & N Raje

  2. Constellation Pharmaceuticals, Inc., Cambridge, MA, USA

    J A Mertz, R J Sims III & M R Cooper

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  1. K T Siu
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  2. J Ramachandran
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Correspondence to N Raje.

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Competing interests

JAM, RJS and MRC are employees and shareholders of Constellation Pharmaceuticals. NR is on advisory boards of Amgen, Bristol-Myers Squibb, Celgene Corporation and Takeda. NR has received research funding from AstraZeneca and Eli Lilly. The remaining authors declare no conflict of interest.

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Siu, K., Ramachandran, J., Yee, A. et al. Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma. Leukemia 31, 1760–1769 (2017). https://doi.org/10.1038/leu.2016.355

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