Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials

Albrecht, Brian K.; Gehling, Victor S.; Hewitt, Michael C.; Vaswani, Rishi G.; Côté, Alexandre; Leblanc, Yves; Nasveschuk, Christopher G.; Bellon, S.F.; Bergeron, Louise; Campbell, Robert M.; Cantone, Nico; Cooper, Michael R.; Cummings, Richard; Jayaram, Hariharan; Joshi, Shivangi; Mertz, Jennifer A.; Neiss, Adrianne; Normant, Emmanuel; O’Meara, Michael; Pardo, Eneida; Poy, Florence; Sandy, Péter; Supko, Jeffrey G.; Sims, Robert J.; Harmange, Jean-Christophe; Taylor, Alexander M.; Audia, James E.

doi:10.1021/acs.jmedchem.5b01882

Cited by 175 publications

(134 citation statements)

References 29 publications

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“…Among them, our current study includes three next-generation BETi (OTX015, CPI-0610, I-BET762) that have been shown to be tolerated in about a half dozen early phase clinical trials as therapies for hematologic malignancies including lymphomas, leukemias, and multiple myeloma, although none of these trials is specific for CTCL (see ClinicalTrials.gov). Durable objective responses (complete and partial) as well as evidence of clinical activity not meeting objective response criteria have been observed [36], [37]. Doses have included the 125- to 250-nM range that showed significant efficacy in our current in vitro and ex vivo studies.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

et al. 2019

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Advanced-stage cutaneous T-cell lymphoma (CTCL) is usually a fatal malignancy despite optimal use of currently available treatments. In this preclinical study of novel CTCL therapy, we performed in vitro and ex vivo experiments to determine the efficacy of combination treatment with a panel of BET bromodomain inhibitors (BETi) (JQ1, OTX015, CPI-0610, I-BET762) and HDAC inhibitors (HDACi) (SAHA/Vorinostat, Romidepsin). BETi/HDACi combinations were synergistic (combination index <1) against cell viability and induced G0/G1 cell cycle arrest. Apoptosis was uniformly enhanced. From a mechanistic standpoint, proliferative drivers c-Myc, Cyclin D1, NFkB, and IL-15Rα were reduced. Inhibitory CDKN1A was increased. CDKN1B, IL-7R, IL-17Rα, STAT3, and STAT5 alterations varied. There were significant increases in extrinsic apoptotic pathway death receptors and ligands (FasL, DR4, DR5, TRAIL, and TNFR1). At clinically tolerable levels of single agents, Romidepsin (1 nM) + OTX015 (125 nM) induced the greatest apoptosis (60%_80%) at 96 hours. Ex vivo studies of leukemic CTCL cells obtained from patients with Sezary syndrome also showed higher levels of apoptosis (about 60%-90%) in response to combination treatments relative to single agents. In contrast, combination treatment of normal CD4+ T cells induced only minimal apoptosis (<10%). Our findings show that the mechanism of action of BETi/HDACi therapy in CTCL involves induction of both cell cycle arrest and apoptosis with reduced proliferative drivers and enhanced expression of apoptotic extrinsic pathway death receptors and ligands. Relative to single agents, the superior anti-CTCL effects of BETi/HDACi combinations in vitro and ex vivo provide a rationale for clinical trials exploring their efficacy as therapy for CTCL.

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Section: Discussionmentioning

confidence: 99%

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

et al. 2019

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“…A dose-dependent decrease of MYC mRNA expression was observed in vivo after PO dosing. Replacement of the thiophene ring in 13 , which has the potential issue of metabolic instability, with a phenyl ring led to compound 4 (Figure 7), 111 which is currently undergoing evaluation in multiple Phase I clinical trials. Compound 4 was approximately 6-fold more potent against BET BD2 (BRD4 BD2 IC 50 = 18 nM) than against BET BD1 (BRD4 BD2 IC 50 = 120 nM).…”

Section: Discovery and Development Of Brd4 Inhibitorsmentioning

confidence: 99%

“…Antitumor effects have also been observed following the use of 4 for treatment of patients with heavily pretreated DLBCL and follicular lymphoma. 111 Various heteroaromatic rings were introduced to the 8-position of 4-( R )-methyl benzoisoxazoleazepine chemotype, which exhibited modest potency in both biochemical and cellular assays. Compound 14 (Figure 7), with an acetamide substituted pyrazole, showed potent BRD4 BD1 inhibition (IC 50 = 17 nM) and significant suppression of MYC expression in MV4-11 cells (IC 50 = 32 nM).…”

Section: Discovery and Development Of Brd4 Inhibitorsmentioning

confidence: 99%

Drug Discovery Targeting Bromodomain-Containing Protein 4

et al. 2017

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BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein–protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective and efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases are also highlighted.

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“…All biochemical assay protocols were carried out as described previously (22)(23)(24). Binding of biotinylated small-molecule ligands to recombinant His-tagged bromodomains was assessed by time-resolved fluorescence resonance energy transfer (TR-FRET).…”

Section: Inhibitor Characterization and Usementioning

confidence: 99%

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Jin¹,

Garcia²,

Chan³

et al. 2017

Cancer Research

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Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castrationresistant prostate cancer. Cancer Res; 77(20); 5564-75. Ó2017 AACR.

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Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials

Cited by 175 publications

References 29 publications

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma

Drug Discovery Targeting Bromodomain-Containing Protein 4

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

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