^
    21d
    Reprogramming oncogenic mitochondria in pancreatic adenocarcinoma through BRD4 inhibition leads to programmed cell death. (PubMed, J Pharmacol Exp Ther)
    Using pharmacological and genetic BRD4 inhibition in PDA patient-derived models, we investigated the effects of BETi on mitochondrial function, mitochondrial protein complex production, ATP production, cellular respiration, autophagy/mitophagy, and murine tumor growth with BMS-986158, a BETi...SIGNIFICANCE STATEMENT: Bromo- and extraterminal domain inhibition is a novel therapeutic strategy for attacking oncogenic mitochondrial behavior in pancreatic ductal adenocarcinoma. Using this strategy in patient-derived models, this study demonstrated a series of mitochondrial-centered events in a temporal sequence leading to cell death and tumor control.
    Journal
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • BRD4 (Bromodomain Containing 4)
    |
    ezobresib (BMS-986158)
    1m
    Identification of BET inhibitors (BETi) against solitary fibrous tumor (SFT) through high-throughput screening (HTS). (PubMed, Neoplasia)
    Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) inhibitors or with ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, this study establishes BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents.
    Journal • PARP Biomarker
    |
    STAT6 (Signal transducer and activator of transcription 6) • NAB2 (NGFI-A Binding Protein 2)
    |
    mivebresib (ABBV 075) • ezobresib (BMS-986158)
    3ms
    Transcriptional Rewiring of BET Inhibitor Treated Ewing Sarcoma Cells Augments their Dependency on Focal Adhesion Kinase. (PubMed, bioRxiv)
    Combining BMS-986158 with the FAK inhibitor Defactinib had synergistic effects, reducing EwS cell proliferation, survival, and invasion in vitro, and significantly inhibited tumor outgrowth in vivo. Our studies identify BET and FAK inhibition as a rational combination therapy worthy of further investigation for EwS, and demonstrate that defining emergent mechanisms of epigenetic drug tolerance can identify new vulnerabilities that can be therapeutically targeted.
    Journal
    |
    FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor)
    |
    Fakzynja (defactinib) • ezobresib (BMS-986158)
    3ms
    NFE2 and PF4 as biomarkers for BET inhibition-induced thrombocytopenia in preclinical and clinical studies. (PubMed, Front Med (Lausanne))
    The consistent downregulation of GATA1, NFE2, and PF4 transcription within hours post-BMS-986158 treatment in both preclinical and clinical studies demonstrates that BET inhibitors induce thrombocytopenia by altering GATA1 gene expression and its downstream genes, NFE2 and PF4, which regulate megakaryopoiesis and thrombopoiesis. Early detection of transcriptional changes in blood samples during treatment courses positions NFE2 and PF4 as promising biomarkers for proactively monitoring and mitigating treatment-emergent thrombocytopenia.
    Preclinical • Journal
    |
    GATA1 (GATA Binding Protein 1) • HEXIM1 (HEXIM P-TEFb Complex Subunit 1)
    |
    ezobresib (BMS-986158)
    3ms
    CA057-003: A Study to Evaluate Safety, Drug Levels and Effectiveness of CC-92480 (BMS-986348) in Combination With Other Treatments in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov)
    P1/2, N=260, Recruiting, Bristol-Myers Squibb | N=160 --> 260
    Enrollment change
    |
    Mekinist (trametinib) • Tazverik (tazemetostat) • mezigdomide (CC-92480) • ezobresib (BMS-986158)
    8ms
    Identification of BET Inhibitors (BETi) Against Solitary Fibrous Tumor (SFT) Through High-Throughput Screening (HTS). (PubMed, bioRxiv)
    Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) or ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, our study established BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents.
    Journal • PARP Biomarker
    |
    STAT6 (Signal transducer and activator of transcription 6) • NAB2 (NGFI-A Binding Protein 2)
    |
    mivebresib (ABBV 075) • ezobresib (BMS-986158)
    1year
    Study of the Bromodomain (BRD) and Extra-Terminal Domain (BET) Inhibitors BMS-986158 and BMS-986378 in Pediatric Cancer (clinicaltrials.gov)
    P1, N=41, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed
    Trial completion
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • BRD4 (Bromodomain Containing 4) • BRD3 (Bromodomain Containing 3)
    |
    MYCN amplification
    |
    ezobresib (BMS-986158) • trotabresib (BMS-986378)
    over1year
    Study of the Bromodomain (BRD) and Extra-Terminal Domain (BET) Inhibitors BMS-986158 and BMS-986378 in Pediatric Cancer (clinicaltrials.gov)
    P1, N=41, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jul 2024 --> Mar 2024
    Trial primary completion date
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • BRD4 (Bromodomain Containing 4) • BRD3 (Bromodomain Containing 3)
    |
    ezobresib (BMS-986158) • trotabresib (BMS-986378)
    over1year
    CA011-023: A Study to Assess the Safety and Tolerability of BMS-986158 Alone and in Combination With Either Ruxolitinib or Fedratinib in Participants With Blood Cancer (Myelofibrosis) (clinicaltrials.gov)
    P1/2, N=216, Active, not recruiting, Bristol-Myers Squibb | Trial completion date: Apr 2027 --> May 2026 | Trial primary completion date: Apr 2025 --> May 2026
    Trial completion date • Trial primary completion date • Combination therapy
    |
    Jakafi (ruxolitinib) • Inrebic (fedratinib) • ezobresib (BMS-986158)
    over1year
    Study of the Bromodomain (BRD) and Extra-Terminal Domain (BET) Inhibitors BMS-986158 and BMS-986378 in Pediatric Cancer (clinicaltrials.gov)
    P1, N=41, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=66 --> 41 | Trial completion date: Jun 2025 --> Jul 2024
    Enrollment closed • Enrollment change • Trial completion date
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • BRD4 (Bromodomain Containing 4) • BRD3 (Bromodomain Containing 3)
    |
    MYCN amplification
    |
    ezobresib (BMS-986158) • trotabresib (BMS-986378)
    over1year
    CA011-023: A Study to Assess the Safety and Tolerability of BMS-986158 Alone and in Combination With Either Ruxolitinib or Fedratinib in Participants With Blood Cancer (Myelofibrosis) (clinicaltrials.gov)
    P1/2, N=216, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting
    Enrollment closed • Combination therapy
    |
    Jakafi (ruxolitinib) • Inrebic (fedratinib) • ezobresib (BMS-986158)
    almost2years
    A Study to Evaluate Safety, Drug Levels and Effectiveness of CC-92480 (BMS-986348) in Combination With Other Treatments in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov)
    P1/2, N=220, Recruiting, Bristol-Myers Squibb | Phase classification: P1b/2a --> P1/2
    Phase classification • Combination therapy
    |
    Mekinist (trametinib) • Tazverik (tazemetostat) • mezigdomide (CC-92480) • ezobresib (BMS-986158)