PLX51107 / Daiichi Sankyo - LARVOL DELTA

CD49d expression is epigenetically regulated in chronic lymphocytic leukemia: Insights from CD49d bimodal cases (ASH 2025) - "Treatment of HG-3 cells with the BRD4 inhibitor PLX51107 (1μM) and the HAT inhibitor Anacardic Acid (50 μM) for 48 hours significantly reduced CD49d transcriptand surface protein levels, confirming their role in regulating CD49d expression.In summary, the longitudinal expansion of CD49d+ cells in CD49d bimodal CLL is driven by bothproliferative advantage and a permissive chromatin landscape at and upstream the ITGA4 locus. Thesefindings provide insight into chromatin-based mechanisms controlling CD49d expression and highlightthe therapeutic potential of targeting this regulatory axis with epigenetic inhibitors."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • BRD4 • EBF1 • ITGA4 • RUNX3

The bromodomain and extra-terminal domain protein BRD4 promotes both self renewal and inflammation in TET2 mutated clonal hematopoiesis (ASH 2025) - "Therefore, we hypothesized BRD4 inhibition would reverse abnormalhematopoiesis in CH via reduction in inflammatory signaling.PBMCs from healthy donors or CCUS patients (n=7 TET2 mutations, 5 with other mutations,12 healthydonors) were cultured with LPS ± the BET inhibitor PLX51107...This signature included genes with roles in neutrophil activation, such as Cd177, Ctsg and Cxcr2,thereby linking altered HSC function to the reduced neutrophil response in DKO mice during emergencygranulopoiesis.In summary, we have identified a critical role for Brd4 in self-renewal, inflammation, and myeloidexpansion in Tet2 mutated CH. Collectively, these results support development of BET inhibitors toprevent progression of high risk CH to MN."

Hematological Disorders • Hematological Malignancies • Inflammation • BRD4 • CCL3 • CD177 • CXCR2 • DUSP1 • IFNG • IL18 • IL1B • IL6 • IRAK1 • ITGAM • NLRP3 • PTPRC • TET2 • TNFA

Acute Myeloid Leukemia Relapse after Bromodomain Inhibitor Treatment or Chemotherapy is Characterized by Myc-Ras Transcriptional Remodeling. (PubMed, bioRxiv) - "Here we show that the BET inhibitor PLX51107 potently suppresses the growth of NRAS -mutant AML cell lines, and that these activities are enhanced by co-treatment with the MEK inhibitor PD0325901. AMLs that relapsed after frontline chemotherapy showed similar transcriptional remodeling. These studies demonstrate transcriptional plasticity in primary AMLs that relapse following in vivo treatment with either targeted agents or chemotherapy, and support evaluating BET inhibition in leukemias with monocytic differentiation and RAS mutations."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • MYC • NRAS

Improving PARP inhibitor efficacy in bladder cancer without genetic BRCAness by combination with PLX51107. (PubMed, Mol Oncol) - "To identify the most suitable PARPi for UC, we compared Olaparib with Talazoparib. In conclusion, we suggest Talazoparib treatment of UC to be highly efficacious on all models examined when combined with PLX51107. This new combination treatment allows efficient application of PARPi Talazoparib to all UC patients, independent of Cisplatin pretreatment and genetic BRCAness."

IO biomarker • Journal • Bladder Cancer • Gene Therapies • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • HRD • SLFN11

Brd4 Inhibition Abrogates Inflammation and Self-Renewal in a Murine Model of Tet2 Mutated Clonal Hematopoiesis (ASH 2023) - "To study pharmacologic Brd4 inhibition in Tet2 KO mice, we utilized PLX51107, a structurally distinct BET inhibitor previously reported on by our laboratory...Our novel inducible double knockout mouse model of CH achieved simultaneous knockout of Brd4 and Tet2, which has never been investigated. Collectively, our data provides rationale for further pre-clinical investigation of BET inhibitors to prevent progression of Tet2 CH."

Preclinical • Hematological Malignancies • Inflammation • Leukemia • Oncology • BRD2 • BRD3 • BRD4 • IL18 • IL1B • IL6 • NLRP3 • TET2 • TNFA

Targeting Inflammation in Tet2 Mutant Clonal Hematopoiesis Via Inhibition of Brd4 Demonstrates Activity in Both Murine and Human Models (ASH 2024) - "Similarly, the BET inhibitor PLX51107 abrogated the increased colony formation (p<0.0001, n=5) and replating (p<0.01, n=5) of Tet2 KO marrow...Further, BETi treatment reduces excess cytokine production in response to LPS in human CCUS. Collectively, these results provide strong rationale for targeting Brd4 in CH at high risk of progression."

Preclinical • Acute Myelogenous Leukemia • Aplastic Anemia • Hematological Disorders • Hematological Malignancies • Inflammation • Leukemia • Oncology • BRD2 • BRD3 • BRD4 • IL18 • IL1B • IL6 • ITGAM • NLRP3 • TET2 • TNFA

Lysine-targeting, Covalent Inhibitors of Bromodomain BD1 of BET Proteins in Live Cells and Animals. (PubMed, Angew Chem Int Ed Engl) - "By further introducing EBA and salicylaldehyde into PLX51107 (a noncovalent BETi), we generated lysine-reactive, irreversible (BDS1-4) and reversible (BDS5-6) BD1 covalent inhibitors. Importantly, BDS4 retained robust activity against fibrosis in cells and animals when compared to RVX-208 (a reported BD2-selective noncovalent inhibitor) which showed only marginal effects. Our work serves as a useful tool to delineate distinct functions of BD1 and BD2 in future studies."

Journal • Fibrosis • Immunology • Oncology • BRD4

Response of urothelial cancer cell lines and their cisplatin-resistant sublines to BET inhibitor PLX51107 in combination with different PARP inhibitors (EACR 2024) - "In this study, we thus investigated potential synergism between BETi PLX51107 and PARPi in UC cell lines (UCCs) and their cisplatin-resistant sublines (LTTs).Material and Methods Dose response curve analyses were performed with BETi PLX51107 (PLX) and PARPi Olaparib (Ola) and Talazoparib (Tala) for RT112, T24 and J82 as well as their LTTs after 72 hours of treatment. Talazoparib proved to be the better PARPi for combination with PLX51107. Thus, we suggest combined treatment with PLX51107 and Talazoparib as a new highly potent treatment option for UC."

Combination therapy • Preclinical • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • BRCA1 • BRCA2

Novel BET Inhibitor PLX51107 for Steroid-Refractory Acute GVHD (clinicaltrials.gov) - P1/2 | N=2 | Terminated | Sponsor: Hannah Choe, MD | Completed ➔ Terminated; Sponsor decision

Trial termination • Acute Graft versus Host Disease • Graft versus Host Disease • Immunology

The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/β-catenin signaling. (PubMed, Exp Hematol Oncol) - "Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BRD4 • CDK9

Novel BET Inhibitor PLX51107 for Steroid-Refractory Acute GVHD (clinicaltrials.gov) - P1/2 | N=2 | Completed | Sponsor: Hannah Choe | Recruiting ➔ Completed | Phase classification: P1b/2 ➔ P1/2 | N=34 ➔ 2 | Trial completion date: Dec 2025 ➔ Sep 2023 | Trial primary completion date: Dec 2024 ➔ Sep 2023

Enrollment change • Phase classification • Trial completion • Trial completion date • Trial primary completion date • Acute Graft versus Host Disease • Graft versus Host Disease • Immunology

Phase 1 Results of Bromodomain and Extraterminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies. (PubMed, Clin Cancer Res) - "In a heavily pre-treated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit."

Combination therapy • IO biomarker • Journal • P1 data • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Malignancies • Hepatology • Infectious Disease • Myelodysplastic Syndrome • Neutropenia • Pneumonia • Respiratory Diseases • BCL2 • BCL2L1 • BRD4 • CD93 • CDK6 • CDKN1A • HEXIM1 • IL7R • MECOM • MYC • TP53

SELECTIVE TARGETING OF BET FAMILY EPIGENETIC REGULATORS IN ADVANCED AND METASTATIC ALVEOLAR RHABDOMYOSARCOMA (CTOS 2023) - "Objective: Standard of care drugs for rhabdomyosarcoma (RMS), such as vincristine and doxorubicin, have a high systemic toxicity and >70% of high-risk patients develop resistance... ARMS cell lines (RH4, RH30) were treated with BETi compounds (BMS-986158, PLX51107) using a 12-point serial dilution (2.6 nM-10 M)... Functional validation confirmed BETi's potential for in vivo ARMS studies. Ongoing clinical trials of the primary drug candidate, BMS-986158, in childhood cancers increases the likelihood of clinical trial opportunities in RMS. Our metastatic models demonstrate clinical relevance and BETi sensitivity, crucial for addressing the lack of established metastatic ARMS studies."

Metastases • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • BRD2 • BRD3 • BRD4 • CASP3 • MYC • PAX3

Phase I Results of Bromodomain and Extra-Terminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies (Clin Cancer Res) - P1 | N=43 | NCT04022785 | "Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1–9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with incomplete platelet recovery (n = 1); morphologic leukemia-free state (n = 2); hematologic improvement (n = 5). The most common nonhematologic toxicities were febrile neutropenia and pneumonia in 12 (32%) patients each; 6 patients (17%) had severe hyperbilirubinemia."

P1 data • Acute Myelogenous Leukemia • Myelodysplastic Syndrome

Phase 1 Results of Bromodomain and Extraterminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies (Clin Cancer Res) - P1 | N=43 | NCT04022785 | "Thirty-seven patients with HR R/R MDS (n=4) and R/R AML (n=33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1-9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with incomplete platelet recovery (n=1); morphological leukemia-free state (n=2); hematologic improvement (n=5)."

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis. (PubMed, Int J Mol Sci) - "Finally, in a collagen-induced arthritis model, PLX51107-treatment reduced FcγR expression in vivo accompanied by a significant reduction in footpad swelling. These results suggest that BET inhibition is a novel therapeutic approach that requires further exploration as a treatment for patients with RA."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Oncology • Rheumatoid Arthritis • Rheumatology • TNFA

Targeting Hippo-YAP, BRD4 and RAS-MAPK interplay in lung cancer to forestall drug resistance (AACR 2023) - "We found a small molecule inhibitor of BET (bromodomain and extra terminal) family proteins (BRD4, 3, 2), PLX51107, suppressed BRAF and KRAS mutant NSCLC cell proliferation and in combination with RAS (KRAS G12C), RAF or MEK inhibitor led to pronounced loss in cell viability with potent MYC downregulation and synergistic apoptosis induction in vitro and potent tumor regression or stasis in vivo in several KRAS mutant CDX and PDX mouse models of NSCLC... This study uncovered a functional interaction between BET proteins, STK11, HIPPO-YAP and RAS-MAPK signaling pathways in lung cancer. These results will help identify combinatorial strategies for treating aberrant RAS-MAPK pathway driven lung cancer more effectively and forestall drug resistance."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BIRC5 • BRAF • BRD4 • KRAS • STK11

Enhanced Anti-Tumor Activity with Exposure to BCL-2 and BRD4 Inhibitors in Mantle Cell Lymphoma (ASH 2022) - "Our data suggests that Venetoclax in combination with PLX51107 exhibits a synergistic effect across a broad range of MCL cell lines. Further elucidation of the mechanism by which PLX51107 and Venetoclax establish synergy is necessary for therapeutic advancement within the field of MCL."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5 • BCL2 • BCL2L1 • BRD4 • CDKN1A • MCL1 • MYC

The Multi-CDK Inhibitor Dinaciclib Shows Synergistic Activity with the BET Inhibitor PLX51107 and Reverses BET Resistance through Inhibition of Canonical Wnt Signaling in Acute Myeloid Leukemia (AML) (ASH 2022) - "These resistant cell lines remained sensitive to dinaciclib treatment and to cytotoxic chemotherapy drugs including cytarabine and etoposide while demonstrating resistance to PLX51107 via Annexin PI and MTS assays. We also found decreased disease burden by bioluminescence and by histopathology in combination treated animals, compared to both vehicle and single agent controls. In conclusion, we have demonstrated in vitro and in vivo synergistic activity of the BET inhibitor PLX51107 in combination with dinaciclib in pre-clinical models of AML and have identified novel inhibition of Wnt / β-catenin signaling by dinaciclib, thereby providing a strategy to circumvent resistance to BET inhibitors in AML."

Acute Myelogenous Leukemia • Gastrointestinal Disorder • Hematological Malignancies • Leukemia • Oncology • Transplantation • BRD4 • CDK9

Episensitation of Cisplatin-Resistant and Naïve Urothelial Carcinoma Cells towards PARP Inhibitor Treatment by BET-Inhibitor PLX51107 (DKK 2022) - "Since Cisplatin-resistant sublines of UCC (LTTs) are highly dependent on DDR and apoptosis resistance, we characterized response of LTTs and treatment naïve parental cells towards combined treatment with PLX51107 and the PARP inhibitor (PARPi) Olaparib. Applicability of PARPi may be extended to BRCA wild-type cancer patients by episensitation with PLX51107. Thus, this combination could be a promising therapeutic option for UC also for second line treat- ment after chemotherapy."

Oncology • Solid Tumor • Urothelial Cancer • BRCA

PLX51107 Enhances the Anti-Tumor Activity of Targeted Therapy in Chronic Lymphocytic Leukemia When Combined with Venetoclax (ASH 2022) - "Conclusion s : Our data indicates that a) PLX51107 has an antitumor effect in CLL cells; b) the combinational treatment of Venetoclax with PLX51107 highly improved the apoptotic effect of single agent treatments. A better understanding of the key signaling pathways for CLL cells' proliferation and survival impacted by BRD4i in combination with Venetoclax would provide a proof-of-concept rationale for studies validating BRD4i as epigenetic approach to target BCR signaling in CLL."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2L1 • BRD2 • BRD3 • BRD4 • BRDT • CCND1 • TP53

Phase 1 Results of Novel Combination Therapy: BET Inhibitor PLX51107 with Azacitidine in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) (ASH 2021) - P1 | "Median prior # therapies = 3 [1-9]; 97% had prior HMA therapy; 84% had prior venetoclax (VEN).17 (46%) pts had prior stem cell transplant (SCT); 7 of whom were on concurrent active immunosuppressive therapy for GVHD prophylaxis at time of enrollment and continued on study (n=6 tacrolimus; n=1 sirolimus). Future directions may include investigation of novel BETi combinations in VEN-naïve pts, further investigation into high-risk subsets of pts with chr 3 abnl/ EVI1/MECOM rearrangements, RUNX1 , and RAS -family mutated pts, and further clinical/translational investigation of BETi activity in leukemia cutis/skin lesions in myeloid malignancies. ClinicalTrials.gov Identifier: NCT04022785."

Clinical • Combination therapy • IO biomarker • P1 data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Fatigue • Gastroenterology • Graft versus Host Disease • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Lymphoma • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Neutropenia • Thrombocytopenia • Transplantation • ASXL1 • BCL2 • BCL2L1 • BRD4 • CDK6 • CDKN1A • HEXIM1 • IL7R • KRAS • MECOM • MYC • NRAS • PTPN11 • RUNX1 • SF3B1 • TP53 • WT1

PLX51107 and Azacitidine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=43 | Completed | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Completed | N=32 ➔ 43

Combination therapy • Enrollment change • Trial completion • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

HDAC inhibitor Vorinostat and BET inhibitor Plx51107 epigenetic agents' combined treatments exert a therapeutic approach upon acute myeloid leukemia cell model. (PubMed, Med Oncol) - "We detected that combined treatment of Plx51107 and Vorinostat strengthened effects detected upon leukemic cells for gaining more sensitization to the agents, decreasing cell proliferation, dramatically inducing apoptosis, and cell cycle arrest; thus regulating target gene expressions. We have shown for the first time that the newly analyzed BRD inhibitor Plx51107 could be a promising therapeutic approach for hematological malignancies and its mono or combined usage might support a rapid transition to clinical trials."

Journal • Acute Myelogenous Leukemia • Gene Therapies • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

SELECTIVELY TARGETING THE EPIGENOME IN EMBRYONAL RHABDOMYOSARCOMA (CTOS 2022) - "Thus, the goal of this study is to explore the molecular mechanisms behind promising epigenetic inhibitors in RMS, focusing on embryonal RMS, and to test these drugs in vivo in combination with vincristine. Our laboratory obtained a selection of epigenetic compounds from the Ontario Institute of Cancer Research (OICR) and Structural Genomics Consortium (SGC) that mainly target BET (BMS-986158, I-BET151, PLX51107) or HDAC (Apicidin, Domatinostat, Fimepinostat) proteins...Furthermore, the level of apoptosis in this cell line was higher after treatment with PLX51107 than after treatment with the positive control, doxorubicin (Figure 3)... Our data suggest that BET inhibitors may exploit an epigenetic weakness of ERMS, perhaps related to MYC amplification. In the future, we plan to conduct transcriptome assays to explore the mechanism of action of BET inhibitors in ERMS, and in vivo drug combination studies in an ERMS mosaic mouse model and patient-derived xenografts (PDXs)."

Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • BRD4 • CASP3 • HDAC1 • MYC