mivebresib (ABBV 075) / AbbVie - LARVOL DELTA

BRD4 Degradation Augments Targeted Alpha Therapy Efficacy in Advanced Prostate Cancer (SNMMI 2026) - "Taken together, these findings support BRD4 targeting as a promising strategy to improve [225Ac]Ac-PSMA responses in mCRPC, where dose escalation is constrained by xerostomia and resistance remains common. We also showed that a PSMA-selected BRD4-degradation approach (IBG-P3, 10 µg/kg) delivers greater therapeutic benefit at ~100-fold lower dose than BET inhibition (ABBV-075, 1 mg/kg) when combined with [225Ac]Ac-PSMA. Comparative mechanistic studies are ongoing to dissect the distinct biological effects of BRD4 inhibition versus degradation, guiding the most effective sensitization path for translation."

Clinical • Metastases • Castration-Resistant Prostate Cancer • Dental Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Xerostomia • BRCA1 • BRCA2 • BRD2 • BRD4 • RAD51 • XRCC2

BRD4 Degradation Augments Targeted Alpha Therapy Efficacy in Advanced Prostate Cancer (SNMMI 2026) - "Taken together, these findings support BRD4 targeting as a promising strategy to improve [225Ac]Ac-PSMA responses in mCRPC, where dose escalation is constrained by xerostomia and resistance remains common. We also showed that a PSMA-selected BRD4-degradation approach (IBG-P3, 10 µg/kg) delivers greater therapeutic benefit at ~100-fold lower dose than BET inhibition (ABBV-075, 1 mg/kg) when combined with [225Ac]Ac-PSMA. Comparative mechanistic studies are ongoing to dissect the distinct biological effects of BRD4 inhibition versus degradation, guiding the most effective sensitization path for translation."

Clinical • Metastases • Castration-Resistant Prostate Cancer • Dental Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Xerostomia • BRCA1 • BRCA2 • BRD2 • BRD4 • RAD51 • XRCC2

Super-Enhancer Formation in Scirrhous Gastric CAFs, and the Presence of a Stromal Field in Non-Cancerous Tissues. (PubMed, Cancer Sci) - "Scirrhous CAFs had heavily acetylated super-enhancers, and therapeutic targeting of super-enhancers by a BET bromodomain inhibitor, mivebresib and JQ-1, markedly decreased their migration-promoting activity. Notably, in scirrhous gastric cancer patients, normal fibroblasts in non-cancerous tissues also had a strong migration-promoting effect. It was suggested that fibroblasts in the non-cancerous tissue of scirrhous gastric patients have already acquired tumor-promoting capacity, forming a stromal field for scirrhous gastric cancer although its spatial extent remains to be solved."

Journal • Gastric Cancer • Oncology • Solid Tumor • CAFs • TGFB1

Small-molecule screening of HiBiT-tagged PAX3::FOXO1 rhabdomyosarcoma cell lines identifies eltanexor as a potent therapeutic agent against fusion-positive rhabdomyosarcoma (AACR 2026) - "The screen identified 183 hits, including Eltanexor, an XPO1 inhibitor. XPO1 exports over 200 proteins from the nucleus by recognizing their nuclear export sequences (NESs). Since the fusion gene retains the NES of FOXO1, a known XPO1 target, we tested whether PAX3::FOXO1 is a substrate."

Preclinical • Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • BRD4 • MYCN • PAX3

Novel therapeutic strategies targeting MECOM rearranged AMLs discovered by unbiased drug screen (AACR 2025) - "Co-targeting with BETi and other identified sensitivities such as the IAP family inhibitor (LCL161) or Bcl-xL inhibitor (navitoclax or A1155463) also exhibited synergistic lethality in 3q26.2-r AML cell lines and PD AML cells. Co-treatment of mivebresib with dactolisib or LCL161 was superior than each drug alone in reducing AML burden and improving survival. These findings demonstrate promising preclinical activity of novel BETi-based combination with IAP or Bcl-xL inhibitor against AML with EVI1 overexpression."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • GATA2 • MECOM • MYC • PIK3CA • TNFA • XIAP

Identifying novel therapies from unbiased screens in AML with MECOM re-arrangement (AACR 2024) - "Consistent with this, co-treatment of mivebresib with SMAC mimetic birinapant or IAP inhibitor LCL161 was synergistically lethal against 3q26.2-r cells. Co-targeting the other identified druggable vulnerabilities from the drug screen with BETi (mTOR/PI3K with BGT-226 and dactolisib, Bcl-xL with navitoclax and A1155463, as well as CBP/p300 (with GNE781, identified through the CRISPR screen), exerted synergistic lethality in 3q26.2-r AML cells...These findings demonstrate promising preclinical activity of BETi and IAP protein or mTOR/PI3K antagonists in the cellular models of AML with EVI1 overexpression. This supports the rationale to determine in vivo efficacy of these BETi-based combinations against this therapy-resistant AML sub-type."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • HEXIM1 • MCL1 • MECOM • mTOR • MYC • PIK3CA • XIAP

Design and evaluation of selective BET PROTACs with potent antitumor efficacy and safety against acute myeloid leukemia. (PubMed, Eur J Med Chem) - "In this work, we designed and synthesized a series of novel BET PROTACs based on the clinical inhibitor ABBV-075. The favorable efficacy-safety balance of A10 underscores its strong potential as a preclinical candidate for AML therapy. This study highlights how rational PROTAC optimization can yield degraders with enhanced therapeutic windows, providing a promising path forward for targeted protein degradation in AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CRBN

Targeted degradation of BRD4 by PROTACs: advances in cancer therapy. (PubMed, Chem Commun (Camb)) - "By integrating BRD4 ligands (JQ1, ABBV-075, and HJB97) with strategies like macrocyclization, dual-targeting designs, and the dTAG system, potency and isoform selectivity have been enhanced. The novel mechanism of molecular glue degraders is also explored. Multidimensional optimization is now propelling BRD4-PROTACs towards clinical translation, promising efficient, safe, and precisely controllable new strategies for cancer treatment."

Journal • Review • Oncology • Targeted Protein Degradation • BRD4 • CRBN

BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML. (PubMed, Leukemia) - "In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations."

Journal • Acute Myelogenous Leukemia • BCL2L1 • BRD4 • GATA2 • MECOM • MYC • PIK3CA • XIAP

Identification of targetable epigenetic vulnerabilities for uveal melanoma. (PubMed, Cell Death Dis) - "Notably, the BET inhibitor mivebresib (ABBV-075) significantly improved survival rates by 50% in a metastatic UM xenograft mouse model and prevented detectable metastases in the bones, spinal cord, and brain...BET and HDAC inhibitors reversed gene expression signatures associated with high metastatic risk and induced a neuron-like phenotype in UM cells. These findings establish BET inhibition as a potent and previously underappreciated vulnerability for metastatic UM."

Journal • Eye Cancer • Hepatocellular Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BAP1 • BRCA

Actionable Findings from an Unbiased Drug Screen for Novel Single Agent and Combination Therapies Against AML with Mecom Re-Arrangement (ASH 2023) - "This was consistent with previous reports that BET inhibitors (e.g., OTX015, mivebresib or ABBV-075 and JQ1) are effective against 3q26.2-r AML cell lines, patient-derived (PD) AML cells and PDX models...In follow-up experiments, XIAP/cIAPs inhibitors birinapant (10-1000 nM) or SM-164 (30-1000 nM), chosen based on the MIPE screen outcomes, induced significantly more dose-dependent apoptosis in 3q26.2-r versus the other AML cell lines...Treatment with the dual mTOR/PIK3CA inhibitor NVP-BGT226 (1-30 nM) or navitoclax or Bcl-xL-specific BH3 mimetic A-1155463 also exerted lethality and synergistically induced apoptosis with mivebresib in AML cells with inv3/t(3; 3)...Co-treatment with birinapant and tegavivint also synergistically induced apoptosis in 3q26.2-r AML cells...Additionally, compared to each drug or vehicle control, co-treatment with birinapant and the BETi OTX015 (30 mg/kg/day, by oral gavage) was more effective in reducing AML burden in the xenograft model...."

Combination therapy • Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • CTNNB1 • GATA2 • HEXIM1 • MCL1 • MECOM • MYC • PIK3CA • SF3B1 • XIAP

Efficacy of Combinations of Targeted Agents Against Dependencies in Mecom Rearranged AML Identified By Unbiased Chemical and CRISPR Screens (ASH 2024) - "Treatment of 3q26.2-r AML cell lines for 96-hours with ORY001 (LSD1i; 3-100 nM), RGFP966 (HDAC3i; 0.5-10 µM) or GNE-781 (CBP/p300i; 10-1000 nM) induced moderate, dose-dependent cell death, as determined by flow cytometry...Treatment of the luciferized 3q26.2-r PD AML242 model, engrafted in NSG mice, with mivebresib (0.5 mg/kg, daily 5x per week), dactolisib (20 mg/kg, daily 5x per week) or LCL161 (65 mg/kg, daily 5x per week) reduced AML burden and increased survival compared to vehicle-treated mice (p < 0.05)...These treatments resulted in reduction of EVI1 and c-Myc levels, associated with preclinical differentiation and apoptotic activity in the 3q26.2-r AML cell models. Further in vivo evaluation of the efficacy of BETi or LSD1i-based combinations against 3q26.2-r AML is warranted."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD4 • CD86 • GATA2 • HDAC3 • ITGAM • MECOM • MYC • PIK3CA • XIAP

Development and Efficacy of a Novel Bromodomain and Extraterminal Domain Degrader K-256 in MYC/BCL2-Related Lymphoma (ASH 2023) - "The GI50 of K-256 in SU-DHL4 and SU-DHL6 was 12.8 nM and 7.50 nM, respectively, and K-256 induced cell death at lower concentrations than existing drugs (vs. JQ1, OTX-015, and ABBV-075, p < 0.0001; vs. dBET6 and ARV-771, p < 0.01)...As expected, the combination of K-256 with venetoclax also demonstrated synergistic effects in PDX cells, similar to those observed in cell lines (CI of 0.515 to 0.762 for inhibiting cell proliferation; 0.085 to 0.995 for inducing apoptosis)... The novel BET degrader, K-256, bound to BET proteins at lower concentrations than existing BET inhibitors and degraders, strongly suppressing MYC expression, primarily via BRD4 degradation. Additionally, K-256 demonstrated superior therapeutic effects in MYC/BCL2-related PDX models both in vitro and in vivo, suggesting that this novel drug could be a promising therapeutic agent for MYC/BCL2-related lymphoma. Its translation to future clinical applications warrants further consideration."

Clinical • IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BRD2 • BRD3 • BRD4 • BRDT • MYC

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 • Hematological Disorders • Hematological Malignancies • Oncology • Sarcoma • Solid Tumor • NAB2 • STAT6

Inhibition of bromodomain and extra-terminal motif (BET) proteins in pediatric sarcoma: A systematic review of in vitro and in vivo studies. (PubMed, Drug Discov Today) - "Accordingly, we reported that ABBV-744 and RVX-208, which selectively target the BD2 domain, and GNE-987, a specific BRD4 degrader, are the most promising inhibitors. However, ABBV-075, a pan-BETi, also exhibits high efficacy, being effective at low doses. Nevertheless, translating these experimental findings into clinical practice remains difficult because of resistance, toxicity, and inconsistent responses. Future approaches include using biomarkers for patient selection, developing isoform-specific BETi, and designing rational combination therapies to enhance treatment for these aggressive pediatric cancers."

Journal • Preclinical • Review • Oncology • Pediatrics • Sarcoma • Solid Tumor • BRD4

DNA Damage Repair Inhibition boots Radiopharmaceutical Therapy for Triple Negative Breast Cancer (EANM 2025) - "Materials and Methods Cytotoxicity was determined in 4T1 cells treated with 0.3 nM -1 mM Talazoparib (TAZ:PARPi), ABBV-075 (BETi), or combined with RPT ([ 177 Lu]Lu-NM600). Median overall survival was 18, 14, 11, 18, 18, 23, and 28 in the vehicle (n=5), PARPi (n=5), BETi (n=5), [ 177 Lu]Lu-NM600 (n=5), [ 177 Lu]Lu-NM600 + BETi (n=5), [ 177 Lu]Lu-NM600 + PARPi (n=5) and [ 177 Lu]Lu-NM600 + PARPi + BETi (n=5), respectively. Conclusion These findings demonstrated the enhance potency of RPT when combined with clinically relevant PARPi and BETi and the potential this combination therapy to tackle TNBC."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • RAD51

Evaluating the Therapeutic Efficacy and Safety of Venetoclax-Based Combination Regimens in Relapsed or Refractory Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis (SOHO 2025) - "Venetoclax-based combinations included various agents such as hypomethylating agents (azacitidine), IDH inhibitors, and investigational drugs like idasanutlin (MDM2 antagonist) and mivebresib (small-molecule pan-BET inhibitor). Venetoclax-based combination regimens demonstrate encouraging efficacy in R/R AML, particularly when combined with azacitidine. However, significant myelosuppressive toxicity highlights the need for careful monitoring."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Synergistic Combination of Radiopharmaceutical Therapy and DNA Damage Repair Inhibition for Triple Negative Breast Cancer (SNMMI 2025) - " Cytotoxicity was determined in 4T1 cells treated with 0.3 nM -1 mM Talazoparib (TAZ: PARPi), ABBV-075 (BETi), or combined with RPT ([177Lu]Lu-NM600). Cell viability was assessed at 24 h, 48 h, 72 h, and 96 h after treatment. IC50s were determined, and combination effects were evaluated between treatments using established synergy models. ABBV-075 showed similar nanomolar cytotoxicity at 72 and 96 h post-treatment (IC50s: 369 vs. 414 nM). Therefore, 300 nM will be used as the reference concentration of ABBV-075 for all subsequent in-vitro combinations."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • RAD51

Multipronged DNA Damage Response Inhibition Enhances the Therapeutic Efficacy of [177Lu]Lu-PSMA-617 in Castration-Resistant Prostate Cancer (SNMMI 2025) - " In vitro cytotoxicity was evaluated in a panel of prostate cancer (PCa) cell lines (PC3-PIP, LNCaP, and 22Rv1) treated with the PARP inhibitor Talazoparib (TAZ), or BET inhibitor ABBV-075, or their combination (0.3 nM–1 mM) using a presto-blue assay. ABBV-075 showed nanomolar cytotoxicity with IC50s (100-300 nM) in PC3-PIP, LNCaP, and 22Rv1 cells. Interestingly, only AR-sensitive 22Rv1 cells responded to TAZ (IC50= 0.7 µM). Synergistic effects were observed for specific TAZ + ABBV-075 treatment combinations in the treated cells (CI>10; HAS and Loewe models)."

Clinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Multipronged DNA Damage Response Inhibition Enhances the Therapeutic Efficacy of [177Lu]Lu-PSMA-617 in Castration-Resistant Prostate Cancer (SNMMI 2025) - " In vitro cytotoxicity was evaluated in a panel of prostate cancer (PCa) cell lines (PC3-PIP, LNCaP, and 22Rv1) treated with the PARP inhibitor Talazoparib (TAZ), or BET inhibitor ABBV-075, or their combination (0.3 nM–1 mM) using a presto-blue assay. ABBV-075 showed nanomolar cytotoxicity with IC50s (100-300 nM) in PC3-PIP, LNCaP, and 22Rv1 cells. Interestingly, only AR-sensitive 22Rv1 cells responded to TAZ (IC50= 0.7 µM). Synergistic effects were observed for specific TAZ + ABBV-075 treatment combinations in the treated cells (CI>10; HAS and Loewe models)."

Clinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Multipronged DNA Damage Response Inhibition Enhances the Therapeutic Efficacy of [177Lu]Lu-PSMA-617 in Castration-Resistant Prostate Cancer (SNMMI 2025) - " In vitro cytotoxicity was evaluated in a panel of prostate cancer (PCa) cell lines (PC3-PIP, LNCaP, and 22Rv1) treated with the PARP inhibitor Talazoparib (TAZ), or BET inhibitor ABBV-075, or their combination (0.3 nM–1 mM) using a presto-blue assay. ABBV-075 showed nanomolar cytotoxicity with IC50s (100-300 nM) in PC3-PIP, LNCaP, and 22Rv1 cells. Interestingly, only AR-sensitive 22Rv1 cells responded to TAZ (IC50= 0.7 µM). Synergistic effects were observed for specific TAZ + ABBV-075 treatment combinations in the treated cells (CI>10; HAS and Loewe models)."

Clinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Synergistic Combination of Radiopharmaceutical Therapy and DNA Damage Repair Inhibition for Triple Negative Breast Cancer (SNMMI 2025) - " Cytotoxicity was determined in 4T1 cells treated with 0.3 nM -1 mM Talazoparib (TAZ: PARPi), ABBV-075 (BETi), or combined with RPT ([177Lu]Lu-NM600). Cell viability was assessed at 24 h, 48 h, 72 h, and 96 h after treatment. IC50s were determined, and combination effects were evaluated between treatments using established synergy models. ABBV-075 showed similar nanomolar cytotoxicity at 72 and 96 h post-treatment (IC50s: 369 vs. 414 nM). Therefore, 300 nM will be used as the reference concentration of ABBV-075 for all subsequent in-vitro combinations."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • RAD51

SORAFENIB REVERSES VENETOCLAX SECONDARY RESISTANCE IN ACUTE MYELOID LEUKAEMIA VIA DOWNREGULATION OF THE RAS-RAF-MEK-ERK SIGNALLING PATHWAY (EHA 2025) - "Peripheral leukemic cells were analysed via flow cytometry, haematological parameters were monitored through blood counts, and spleen size was measured post-treatment.High-throughput in vitro drug sensitivity screening identified six venetoclax-synergistic agents from thirty-one candidates: ruxolitinib, sorafenib, A1331852, mivebresib, quizartinib, and nilotinib. Sorafenib reverses secondary venetoclax resistance in AML by inhibiting the Ras-Raf-MEK-ERK pathway and downregulating anti-apoptotic proteins (BCL-2, MCL-1, BCL-XL), thereby synergising with venetoclax to inhibit resistant leukaemic cells. This study provides a promising therapeutic strategy for overcoming venetoclax resistance in AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • MCL1

An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains the stemness and malignancy of diffuse intrinsic pontine glioma. (PubMed, Nat Commun) - "Intriguingly, disrupting CREB5 super-enhancers with ABBV-075 significantly reduces its expression and inhibits H3.3K27M DIPG tumor growth. Combined treatment with ABBV-075 and a BRG1 inhibitor presents a promising therapeutic strategy for clinical translation in H3.3K27M DIPG treatment."

Journal • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CREB5 • ID1 • SMARCA4

Exploring BET inhibitors as promising agents for solitary fibrous tumor (Sarcoma-RC 2025) - "RNA-seq was performed on Illumina NovaSeq X. Results Among seven BETis tested in SFT cells, Mivebresib and BMS-986158 exhibited the lowest IC50 values (INT-SFT: 10.8 nM and 6.23 nM; IEC139: 12.5 nM and 28.8 nM) and, in contrast to other BETis, induced apoptosis at 50 nM (INT-SFT: 32% and 45.9%; IEC139: 27.5% and 34.3%)...Combining BETis with PARPi rucaparib or ATRi berzosertib showed synergistic effects, enhancing apoptotic responses and DNA damage accumulation...In vivo, Mivebresib markedly reduced tumor growth in SFT PDX models, supporting its potential as a targeted therapy. Legal entity responsible for the study The authors."

Oncology • Sarcoma • Solid Tumor • CCND1 • CDKN1A • NAB2 • STAT6