ABBV-744
/ AbbVie
- LARVOL DELTA
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November 18, 2024
The KLF16/MYC feedback loop is a therapeutic target in bladder cancer.
(PubMed, J Exp Clin Cancer Res)
- "Our study revealed the crucial role of the KLF16/MYC regulatory axis in modulating tumor growth and chemotherapy sensitivity in BLCA, suggesting that combining bromodomain inhibitors, such as OTX015 or ABBV-744, with DDP or gemcitabine could be a promising therapeutic intervention for BLCA patients."
Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • DUSP1
June 18, 2024
Safety and Tolerability Study of Oral ABBV-744 Tablet Alone or in Combination With Oral Ruxolitinib Tablet or Oral Navitoclax Tablet in Adult Participants With Myelofibrosis
(clinicaltrials.gov)
- P1 | N=21 | Active, not recruiting | Sponsor: AbbVie | Phase classification: P1b ➔ P1 | Trial completion date: Jul 2024 ➔ Nov 2024 | Trial primary completion date: Jul 2024 ➔ Nov 2024
Combination therapy • Phase classification • Trial completion date • Trial primary completion date • Myelofibrosis • Neutropenia
June 12, 2024
ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis.
(PubMed, Acta Pharmacol Sin)
- "We demonstrated that pretreatment of ABBV-744 significantly reduced the expression levels of basic leucine zipper ATF-like transcription factor 2 (BATF2) and interferon regulatory factor 4 (IRF4), and suppressed JAK-STAT signaling pathway in LPS-stimulated BV-2 cells and mice, suggesting that the anti-neuroinflammatory effect of ABBV-744 might be associated with regulation of BATF2-IRF4-STAT1/3/5 pathway, which was confirmed by gene knockdown experiments. This study demonstrates the effect of a BD2 high selective BET inhibitor, ABBV-744, against microglial inflammation, and reveals a BATF2-IRF4-STAT1/3/5 pathway in regulation of microglial inflammation, which might provide new clues for discovery of effective therapeutic strategy against neuroinflammation."
Journal • Inflammation • IL1B • IL6 • IRF4 • STAT1 • TNFA
March 26, 2024
Machine learning-aided search for ligands of P2Y6 and other P2Y receptors.
(PubMed, Purinergic Signal)
- "The hit compound ABBV-744, an experimental anticancer drug with a 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine scaffold, had multifaceted interactions with the P2YR family: hP2Y6R inhibition in a non-surmountable fashion, suggesting that noncompetitive antagonism, and hP2Y1R enhancement, but not hP2Y14R binding inhibition. Other machine learning-selected compounds were either weak (experimental anti-asthmatic drug AZD5423 with a phenyl-1H-indazole scaffold) or inactive in inhibiting the hP2Y6R. Experimental drugs TAK-593 and GSK1070916 (100 µM) inhibited P2Y14R fluorescent binding by 50% and 38%, respectively, and all other compounds by < 20%. Thus, machine learning has led the way toward revealing previously unknown modulators of several P2YR subtypes that have varied effects."
Journal • Machine learning • Asthma • Astrocytoma • Brain Cancer • CNS Disorders • Immunology • Metabolic Disorders • Oncology • Respiratory Diseases • Solid Tumor
November 03, 2023
Pre-Clinical Efficacy of CDK7 Inhibitor-Based Combinations in Cellular Models of Advanced Myeloproliferative Neoplasms (MPN) Transformed to AML
(ASH 2023)
- "Treatment with JAK inhibitor (JAKi), e.g., ruxolitinib, venetoclax or hypomethylating agents alone or in combination are ineffective in improving the poor survival in MPN-sAML...Present studies demonstrate that treatment with ATP-competitive, covalent CDK7 inhibitors (CDK7i) SY-1365, and clinical grade SY-5609, dose-dependently (20 to 250 nM) increased % G1 while reducing the % of cell-cycle S phase SET2 and HEL cells...SY-5609 treatment also exerted synergistic lethality with the BETi pelabresib or BD2-selective BETi ABBV-744 or the CBP/p300 inhibitor GNE-049 in MPN-sAML cells...Additionally, compared to each drug or vehicle control, co-treatment with SY-5609 and OTX015 (30 mg/kg/day by oral gavage) reduced more MPN-sAML burden and significantly improved survival in a HEL-Luc/GFP xenograft model without inducing toxicity. These findings demonstrate promising preclinical activity of CDK7 inhibition against the cellular models of MPN-sAML, supporting the rationale to..."
Metastases • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ASXL1 • AURKA • BCL2L1 • BRD4 • CALR • CASP9 • CCND1 • CD123 • CD34 • CD99 • CDK1 • CDK4 • CDK6 • CDK9 • CDKN1A • CLEC12A • HEXIM1 • IL3RA • ITGAM • JAK2 • MCL1 • MYC • PIM1 • PLK1 • RUNX1 • SRSF2 • STAT5 • TET2 • TGFB1
December 11, 2023
Treatment of anemia in myelofibrosis: focusing on Novel Therapeutic Options.
(PubMed, Expert Opin Investig Drugs)
- "This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat. Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination."
Journal • Review • Anemia • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • BCL2 • BCL2L1
September 29, 2023
ABBV-744 induces autophagy in gastric cancer cells by regulating PI3K/AKT/mTOR/p70S6k and MAPK signaling pathways.
(PubMed, Neoplasia)
- "In vivo mouse xenograft studies demonstrated that ABBV-744 significantly suppressed the growth of gastric cancer cells via inducing autophagy. Taken together, our results suggest that ABBV-744 is a novel drug candidate for gastric cancer."
Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor
August 16, 2023
EFFICACY OF BET INHIBITORS IN SOLITARY FIBROUS TUMOR: AN IN VITRO EVALUATION
(CTOS 2023)
- " Three different BET inhibitors, Mivebresib, Pelabresib, and ABBV-744, were evaluated to determine their antitumor activity in SFT cell lines...In addition, a synergistic effect was observed between BET inhibitors and Rucaparib, a commonly used PARP inhibitor (Combination Index of 0.42 and 0.27 for INT-SFT and IEC139 respectively)... BET inhibitors demonstrated efficacy and specificity for SFT in vitro models, potentially through targeting the HR pathway. Further investigations, including in vivo experiments, are necessary to elucidate the underlying mechanisms and evaluate clinical efficacy. The knowledge gained from these studies can lay the groundwork for potential clinical trials that will enable us to assess their safety, efficacy, and potential side effects in the context of SFT."
Preclinical • Leiomyosarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • H2AX • NAB2 • RAD51 • STAT6
October 01, 2023
Safety and Tolerability Study of Oral ABBV-744 Tablet Alone or in Combination With Oral Ruxolitinib Tablet or Oral Navitoclax Tablet in Adult Participants With Myelofibrosis
(clinicaltrials.gov)
- P1b | N=21 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting | N=130 ➔ 21
Combination therapy • Enrollment change • Enrollment closed • Myelofibrosis • Neutropenia
September 25, 2023
Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations.
(PubMed, ACS Omega)
- "This study determined the effectiveness of pyrrolopyridone analogues to selectively inhibit BD2 using a pan-BD inhibitor (ABBV-075) and a selective-BD2 inhibitor (ABBV-744). These results suggest that the R3 and R5 regions of pyrrolopyridone analogues can be modified to improve the selectivity between BRD4-BD1 and BRD4-BD2. The selectivity of BD2 inhibition by pyrrolopyridone analogues can be used to design novel BD2 inhibitors based on a pyrrolopyridone core."
Journal • BRD4
August 26, 2023
BRD4 Inhibition as a Strategy to Prolong the Response to Standard of Care in Estrogen Receptor-Positive Breast Cancer.
(PubMed, Cancers (Basel))
- "ARV-825 was effective in both p53 wild-type (WT) breast tumor cells and in cells lacking functional p53 either alone or in combination with tamoxifen, while the effectiveness of ABBV-744 was limited to fulvestrant plus palbociclib in p53 WT cells. These differential effects may be related to the capacity to suppress c-Myc, a downstream target of BRD4."
Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRD4 • ER • MYC
May 12, 2023
ABBV-744 ALONE OR IN COMBINATION WITH RUXOLITINIB OR NAVITOCLAX IN PATIENTS WITH MYELOFIBROSIS: A PHASE 1B STUDY
(EHA 2023)
- P1b | "The Janus kinase inhibitors (JAKis) ruxolitinib and fedratinib are approved for the treatment of MF based on reduction of symptomatology and splenomegaly, however, not all patients respond. Clinical trial, Myelofibrosis"
Clinical • Combination therapy • P1 data • Hematological Malignancies • Immunology • Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm • Non-Hodgkin’s Lymphoma • Oncology
June 06, 2023
Selective BD2 Inhibitor Exerts Anti-Fibrotic Effects via BRD4/FoxM1/Plk1 Axis in Orbital Fibroblasts From Patients With Thyroid Eye Disease.
(PubMed, Invest Ophthalmol Vis Sci)
- "Inhibition of BRD4 both by BD2 selective inhibitor ABBV744 and pan-BET inhibitor JQ1 exerted anti-fibrotic effects, whereas ABBV744 displayed superior anti-fibrotic effects and acceptable safety compared to JQ1. We conclude that BDR4 may modulate the profibrotic process in OFs of patients with TED via the FoxM1/Plk1 axis, and that selectively targeting BD2 domain of BRD4 may therefore be a potential therapeutic option for treating patients with TED."
Journal • Fibrosis • Ophthalmology • Thyroid Eye Disease • BRD4 • FOXM1 • PLK1 • TGFB1
April 11, 2023
Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens.
(PubMed, Proc Natl Acad Sci U S A)
- "Based on this observation, a combination therapy regimen inhibiting both BET and GSK3 was developed to impede KMT2A-r leukemia progression in patient-derived xenografts in vivo. Our results revealed molecular mechanisms underlying BETi resistance and a promising combination treatment regimen of ABBV-744 and CHIR-98014 by utilizing unique ex vivo and in vivo KMT2A-r PDX models."
Journal • Hematological Malignancies • Leukemia • Oncology • KMT2A • SPOP
November 07, 2019
Selective Targeting BET Family Bdii Bromodomain with Abbv-744 and BCL-2 with Venetoclax (ABT-199) Is Synergistic in Primary Acute Myeloid Leukemia Models
(ASH 2019)
- P1; "First generation BET inhibitor ABBV-075 and Venetoclax were recently shown to be synergistic in AML cell lines (Bui MH, Cancer Res 2017)...The gene expression analysis indicated that the genes differentially expressed in the synergy vs. low apoptosis samples overlap with the genes inhibited by dual BCL-2/BCL-XL inhibitor ABT-737...In summary, combinatorial blockade of BDII bromodomain and of BCL-2 anti-apoptotic pathway facilitates apoptotic cell death, suppresses proliferation in the majority of primary AML cells and produces anti-AML activity in AML PDX models in vivo at tolerable doses of both agents. This combination is currently undergoing testing in a Phase I clinical trial in AML (NCT03360006)."
IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CASP3 • CCND1 • DNMT3A • EGFR • FLT3 • GADD45A • IDH1 • IL1R1 • MYC • NPM1 • PARP
November 04, 2022
Bruton's Tyrosine Kinase (BTK) Degrader Nx-2127 Exhibits Lethal Activity and Synergy with Venetoclax and BET Protein Inhibitor Against MCL Cells Sensitive or Resistant to Covalent BTK Inhibitors
(ASH 2022)
- "Covalent BTK inhibitors (BTKis), including ibrutinib and acalabrutinib, irreversibly bind to cysteine 481 in the kinase domain of BTK, inhibit growth, and induce loss of viability of MCL cells...In the present studies, we determined that in vitro exposure of human MCL cells, including MCL cell lines: REC1, Mino and JeKo-1, as well as patient-derived (PD) MCL cells, to NX-2127 (10 to 250 nM) for 2 to 24 hours markedly depleted BTK levels via proteasomal degradation, since co-treatment with the proteasome inhibitor carfilzomib restored BTK levels. NX-2127 but not NX-5948 treatment also degraded and depleted IKZF1 and IKZF3 levels...Co-treatment with NX-2127 (10 to 100 nM) and low nM levels of venetoclax or ABBV-744 was synergistically lethal against MCL cells (Delta synergy score above 1.0 by ZIP method). Collectively, these findings demonstrate that treatment with NX-2127 degrades and attenuates BTK and IKZF1/3 levels, as well as inhibits the downstream pro-growth and..."
IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • BIRC3 • CARD11 • CCND1 • CRBN • IKZF1 • IKZF3 • IL10 • MAP3K14 • PLCG2 • SOX11 • TNFA
December 09, 2022
Safety and Tolerability Study of Oral ABBV-744 Tablet Alone or in Combination With Oral Ruxolitinib Tablet or Oral Navitoclax Tablet in Adult Participants With Myelofibrosis
(clinicaltrials.gov)
- P1b | N=130 | Recruiting | Sponsor: AbbVie | Trial primary completion date: Nov 2022 ➔ Jul 2024
Combination therapy • Trial primary completion date • Myelofibrosis
November 07, 2022
ABBV-744 alone or in combination with ruxolitinib or navitoclax in patients with myelofibrosis: a phase 1b study
(IMPN 2022)
- No abstract available
Clinical • Combination therapy • P1 data • Myelofibrosis
August 09, 2022
Discovery of HCV NS5A inhibitors ombitasvir (ABT-267) and pibrentasvir (ABT-530) and bromodomain and extra-terminal domain (BET) inhibitors mivebresib (ABBV-075) and ABBV-744
(ACS-Fall 2022)
- "Our initial medicinal chemistry exploration of HCV NS5A resulted in the discovery of ombitasvir (ABT-267), the HCV NS5A inhibitor that is a key component of Viekira Pak, AbbVie’s 1st generation treatment for HCV. Further research culminated in the discovery of pibrentasvir (ABT-530), the HCV NS5A inhibitor that is a key component of Mavyret, AbbVie’s 2nd generation treatment for HCV...Structure-based drug design at AbbVie led to the discovery of a novel and potent pan BET inhibitor, mivebresib (ABBV-075, phase 1). Additional effort led to the discovery of the BD2 selective BET inhibitor ABBV-744 (phase 1)."
Hepatitis C • Hepatology • Infectious Disease • Inflammation • Oncology
June 24, 2022
Co-clinical Modeling of the Activity of the BET Inhibitor Mivebresib (ABBV-075) in AML.
(PubMed, In Vivo)
- "These findings confirm the validity of the model system in the co-clinical setting, establish highly relevant in vivo models for the discovery of cancer therapy, and indicate the therapeutic value of BET inhibitors for AML and, potentially, myelofibrosis treatment."
Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelofibrosis • Oncology
January 15, 2022
BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2.
(PubMed, Nat Cell Biol)
- "Moreover, pharmacological BRD2 inhibition with the drug ABBV-744 inhibited SARS-CoV-2 replication in Syrian hamsters. We also found that BRD2 controls transcription of several other genes induced upon SARS-CoV-2 infection, including the interferon response, which in turn regulates the antiviral response. Together, our results pinpoint BRD2 as a potent and essential regulator of the host response to SARS-CoV-2 infection and highlight the potential of BRD2 as a therapeutic target for COVID-19."
Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases
November 05, 2021
Interrogating Novel Bromodomain Inhibition Resistance Mechanism in Mllr Leukemia
(ASH 2021)
- "By conducting genome-wide and targeted loss-of-function CRISPR screens using MLLr AML cell lines upon BETi treatment including ABBV-744, JQ1, and dBET1, we discovered that Speckle Type POZ (SPOP) gene deficiency leads to significant BETi resistance in in vitro cell culture systems (SEM, OCI-AMl2 and MV4,11), and by in vivo transplantation of human MLLr leukemia SEM cells into immune-deficient mice. Targeting GSK3A/3B pathways by ChIR-98014 can overcome SPOP-associated BETi resistance in in vivo preclinical models of MLLr leukemia. Successful outcomes following combination therapy using ChIR-98014 and BETi in PDX models would translate to a clinical application that holds the promise to cure MLLr leukemia."
Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Targeted Protein Degradation • Transplantation • BRD4 • PTPRC • SPOP • TRIM24
November 05, 2020
[VIRTUAL] Two Phase 1b Studies Evaluating the Safety and Tolerability of BET Inhibitors, ABBV-744 and Mivebresib, as Monotherapies and in Combination with Ruxolitinib or Navitoclax in Patients with Myelofibrosis
(ASH 2020)
- P1b | "Confidence intervals will be derived from the Clopper Pearson method. First dosing is planned for Q4 2020."
Clinical • Combination therapy • P1 data • Hematological Disorders • Immunology • Inflammation • Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Solid Tumor • Transplantation • BCL2L1
October 01, 2021
From Hit Seeking to Magic Bullets: The Successful Union of Epigenetic and Fragment Based Drug Discovery (EPIDD + FBDD).
(PubMed, J Med Chem)
- "The greatest successes to date are in prospecting for bromodomain binding ligands. From a diverse array of fragment hits, multiple potent and selective compounds ensued, including the oncology clinical candidates mivebresib, ABBV-744, pelabresib, and PLX51107."
Journal • Oncology
July 14, 2021
Selective inhibition of the second bromodomain of BET family proteins results in robust antitumor activity in preclinical models of acute myeloid leukemia.
(PubMed, Mol Cancer Ther)
- P1 | "Studies in AML xenograft models demonstrated anti-tumor efficacy for ABBV-744 that was comparable to the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced anti-tumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared to monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006)."
Journal • Preclinical • Acute Myelogenous Leukemia • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Prostate Cancer • Solid Tumor • Thrombocytopenia • AR • BRD4
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