- |||||||||| mocetinostat (MGCD0103) / Otsuka, BMS, CUDC-101 / Curis, pracinostat (SB939) / Helsinn, MEI, Menarini
Journal: HDAC Inhibitors Can Enhance Radiosensitivity of Head and Neck Cancer Cells Through Suppressing DNA Repair. (Pubmed Central) - Dec 17, 2024
We also demonstrated that this combinatorial strategy leads to inhibition of the repair of DNA double-strand breaks through the neutral comet assay and ?H2AX foci analysis using immunofluorescence microscopy, providing a mechanism of action through which HDAC inhibition functions in HNSCC radiosensitisation. We believe that this approach should be further investigated in preclinical models, in order to realise the full therapeutic potential of HDAC inhibition for the radiosensitisation of HNSCC, eventually leading to improved patient treatment efficacy and outcomes.
- |||||||||| abexinostat (CG-781) / Xynomic, pracinostat (SB939) / Helsinn, MEI, Menarini, EPZ015666 / GSK, Ipsen
Three novel epigenetic-modifying compounds identified as HIV latency-reversing agents in Ghana (Convention Center - Hall I-1 (1st Floor); In-Person-Only) - Oct 11, 2024 - Abstract #ASTMH2024ASTMH_1607;
These compounds effectively reactivated latent HIV-1 in vitro and induced HIV expression ex vivo. Our findings suggest that these LRAs hold promise for reactivating latent HIV in individuals living with the virus.
- |||||||||| LOW DOSE DOUBLE EPIGENETIC THERAPY IMPROVES IMMUNOTHERAPY RESPONSE AND PROLONGS SURVIVAL IN PANCREATIC CANCER. (103AB - Walter E. Washington Convention Center) - Mar 14, 2024 - Abstract #DDW2024DDW_2386;
We previously showed, using the KPC (Kras LSL G12D/+; p53 r172H/+; Pdx1-Cre) mouse model of pancreatic cancer (PDAC), that sequential treatment with the DNA hypomethylating agent (HMA) decitabine (DAC) followed by aPD-1 initially enhanced anti-tumor effects, yet tumors developed resistance linked to a unique M2-polarized Chil3+ myeloid subtype...We then evaluated four different HDAC inhibitors with reported immunomodulatory effects and non-overlapping HDAC isoform specificities: Romidepsin (RM), Domatinostat (DM), Pracinostat (PR) and Entinostat (EN)...Our findings identify a functionally immune suppressive HMA specific myeloid effect. The addition of a second epigenetic agent enhances the therapeutic efficacy resulting in prolonged survival and reverses the suppressive myeloid cell related effects of DAC + aPD1.
- |||||||||| Increasing the therapeutic vulnerability of heterogenous cell phenotypes within prostate cancer (Section 13) - Mar 5, 2024 - Abstract #AACR2024AACR_7394;
Funding was provided by the University of Arizona Cancer Center (NCI-P30 CA23074 and NCI-R01 CA159406) and by the Partnership in Native American Cancer Prevention at the University of Arizona (U54CA143924) and Northern Arizona University (U54CA143925). Collaborators at NCATS were supported by the intramural research program.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini
Journal: ALDH1A3 contributes to tumorigenesis in high-grade serous ovarian cancer by epigenetic modification. (Pubmed Central) - Mar 4, 2024
CHIP assay demonstrated a significant enrichment of H3K27ac at the PITX1 promoter, and ALDH1A3 knockdown reduced the binding between H3K27ac and PITX1. Taken together, our data suggest that ALDH1A3, transcriptional activated by HIF-1?, promotes tumorigenesis and decreases chemosensitivity by increasing H3K27ac of PITX1 promoter in HGSOC.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini
Journal: HDAC inhibitor SB939 potentiates TRAIL-induced apoptosis in colorectal cancer cells. (Pubmed Central) - Aug 16, 2023
The ability of SB939 to sensitize HT-29 cells suggests that SB939 can induce essential changes in cell signaling pathways. Thus, the pan-HDAC inhibitor SB939 sensitizes TRAIL-induced apoptosis via up-regulation of DR5, and SB939-TRAIL combined treatment may target the MAPK pathways and serve as an effective therapeutic strategy against CRC.
- |||||||||| Dual Targeting of MDM2 and BCL2/Bclxl Demonstrates Potent Synergistic Activity in High-Risk Adult Acute Lymphoblastic Leukemia (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_5948;
These included clinical ALL drugs dexamethasone and daunorubicin, proteasome inhibitor carfilzomib, BCL2/BCLxL inhibitor navitoclax, and histone deacetylase inhibitors romidepsin and pracinostat...Combination of idasanutlin with navitoclax exhibited both the greatest and most consistent synergistic interaction (d = 24.7±8.7, n=11) of the candidate combinations (n=10) across an extensive landscape of dose combinations; additionally alluding to synergy indiscriminate of ALL subtype...Together, we provide strong evidence that concurrent targeting of MDM2-p53 binding and BCL2/BCLxL leads to potent and synergistic enhancement of apoptotic cell death in a range of high-risk ALL subtypes. The proposed combination of two clinical-stage compounds could have considerable positive clinical impact for the treatment of adult ALL.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini
Journal, Epigenetic controller: The novel histone deacetylase inhibitor pracinostat suppresses the malignant phenotype in human glioma. (Pubmed Central) - Jul 27, 2022
A number of phytochemicals and synthetic and biological molecules have demonstrated potential inhibitory effects on JAK and STAT3, thereby paving the way for the development of better therapeutics against BC. Our results strongly support the potential clinical use of pracinostat as a novel therapy for human glioma in the near future.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini, Mylotarg (gemtuzumab ozogamicin) / UCB, PDL, Pfizer
Trial completion, Combination therapy: Pracinostat and Gemtuzumab Ozogamicin (PraGO) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - Jun 30, 2022
P1, N=14, Completed,
Our results strongly support the potential clinical use of pracinostat as a novel therapy for human glioma in the near future. Active, not recruiting --> Completed
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini
MYBLOCK: A MYELOID BLOOD CANCER INITIATIVE () - May 13, 2022 - Abstract #EHA2022EHA_652;
Triple combinations involving a backbone of idarubicin and pracinostat with the addition of patient specific third agent has shown sensitivity. Conclusion Moving forward with the MYBLOCk initiative we will build a database of mutational information alongside sensitivity to the MYBLOCk panel to allow the rapid identification of personalised therapeutic options highlighting more effective, and novel, combinations for a wider range of patients at diagnosis.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini, GSK2879552 / GSK
Journal: BCL11A promotes myeloid leukemogenesis by repressing PU.1 target genes. (Pubmed Central) - Apr 27, 2022
High BCL11A expression is associated with worse prognosis in human AML patients. Blocking of BCL11A expression upregulates the expression of PU.1 target genes, and inhibits the growth of HL-60 cells and their engraftment to the bone marrow, suggesting that BCL11A is involved in human myeloid malignancies via the suppression of PU.1 transcriptional activity.
- |||||||||| Journal: Integrative Analysis for Identification of Therapeutic Targets and Prognostic Signatures in Non-Small Cell Lung Cancer. (Pubmed Central) - Apr 19, 2022
On the contrary, high mRNA expressions of CBL, FYN, LRKK2, and SOCS2 were associated with a significantly better prognosis. Furthermore, our drug target analysis for these hub genes suggests a potential use of Trichostatin A, Pracinostat, TGX-221, PHA-793887, AG-879, and IMD0354 antineoplastic agents to reverse the expression of these DEGs in NSCLC patients.
- |||||||||| Journal: E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors. (Pubmed Central) - Jan 12, 2022
Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1 murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic CDH1-deficient cancers.
- |||||||||| Review, Journal: HDAC6 as privileged target in drug discovery: A perspective. (Pubmed Central) - Nov 21, 2021
Though several HDAC6 inhibitors (HDAC6is) have been developed till date, only two ACY-1215 (ricolinostat) and ACY-241 (citarinostat) are in the clinical trials...This review details the study about the structural biology of HDAC6, its physiological and pathological role in several disease states and the detailed structure-activity relationships (SARs) of the known HDAC6i. This detailed review will provide key insights to design novel and highly effective HDAC6i in the future.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini, Mylotarg (gemtuzumab ozogamicin) / UCB, PDL, Pfizer
Enrollment closed, Combination therapy: Pracinostat and Gemtuzumab Ozogamicin (PraGO) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - Oct 18, 2021
P1, N=14, Active, not recruiting,
The randomized phase 2 part of this tandem triplet strategy with the goal of preventing adaptive resistance is underway. Recruiting --> Active, not recruiting
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini, Mylotarg (gemtuzumab ozogamicin) / UCB, PDL, Pfizer
Trial completion date, Trial primary completion date, Combination therapy: Pracinostat and Gemtuzumab Ozogamicin (PraGO) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - May 18, 2021
P1, N=18, Recruiting,
Our study provides novel insights into the antilymphoma activity of pracinostat and identifies a differential response of DLBCL metabolic subtypes to HDACis. Trial completion date: Mar 2022 --> Mar 2023 | Trial primary completion date: May 2021 --> May 2022
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini
Journal: Characterizing binding intensity and energetic features of histone deacetylase inhibitor pracinostat towards class I HDAC isozymes through futuristic drug designing strategy. (Pubmed Central) - Feb 26, 2021
Currently, no energetic and structural studies are available about the pracinostat against four HDAC isozymes of Class I. Taking this into account, the current study involved flexible molecular docking for gaining insights regarding pracinostat-HDAC isozyme interactions, molecular mechanics generalized born surface area (MM-GBSA) for estimating binding affinity of this inhibitor towards these isozymes and energetically optimized pharmacophores (e-Pharmacophores) technique for delineating the critical e-pharmacophoric features of pracinostat in its least energy state in the binding pocket of these HDACs. The outcome from this study will help in further optimization of pracinostat towards better therapeutic and the e-Pharmacophores generated will serve as queries in e-Pharamcophores guided virtual screening.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini
Trial completion, Trial completion date, Trial primary completion date: A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes (clinicaltrials.gov) - Feb 15, 2021
P2, N=60, Completed,
The outcome from this study will help in further optimization of pracinostat towards better therapeutic and the e-Pharmacophores generated will serve as queries in e-Pharamcophores guided virtual screening. Active, not recruiting --> Completed | Trial completion date: Jun 2020 --> Dec 2020 | Trial primary completion date: Mar 2020 --> Dec 2020
- |||||||||| Leustatin (cladribine) / J&J
[VIRTUAL] Novel Combination Drug Regimens Using Hypomethylating Agents in Treatment of Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia () - Nov 5, 2020 - Abstract #ASH2020ASH_4981;
In addition, three studies compared outcomes of CDR involving decitabine with all trans retinoic acid (ATRA)(n=93, ORR=21.9% vs 13.5%, p=0.06; mOS= 8.2 m vs 5.1 m, p=0.006) or talacotuzumab (CR/CRi= 15% vs 11%, p=0.44; mOS= 5.36 m vs 7.26 m, p=0.78) or bortezomib (CR/CRi= 39% vs 38%, p=0.91, mOS=9.3 m vs 8.9,p=0.18) to decitabine alone...Drugs included midostaurin (n= 88 , CR/CRi=25-29% mOS= 6-8 m) and pracinostat (n= 50, CR/CRi =46% mOS=19.1 m), In addition, two studies compared outcomes using CDR involving AZA with panobinostat (n=22, CR= 22.4 vs 30.8%, OS at 1 year = 60% vs 70%) or entinostat (n=18, ORR= 0% vs 16.6%, mOS=6 m vs 13 m) to AZA alone...The above listed efficacious CDR involving decitabine in phase I/II studies need to be evaluated in large, randomized trials to assess for definitive benefit. If proven efficacious in larger studies, they could serve as additional first line CDR options in addition to HMA and venetoclax in treating elderly patients with newly diagnosed AML.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini
Trial completion date, Trial termination, Trial primary completion date, Combination therapy: PRIMULA : An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia (clinicaltrials.gov) - Sep 9, 2020
P3, N=406, Terminated,
Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design. Trial completion date: May 2021 --> Aug 2020 | Recruiting --> Terminated | Trial primary completion date: May 2021 --> Aug 2020; The IDMC recommended to stop the study prematurely due to a lack of efficacy.
- |||||||||| Journal: Drug repurposing screen identifies novel classes of drugs with anticancer activity in mantle cell lymphoma. (Pubmed Central) - Sep 2, 2020
Trial completion date: May 2021 --> Aug 2020 | Recruiting --> Terminated | Trial primary completion date: May 2021 --> Aug 2020; The IDMC recommended to stop the study prematurely due to a lack of efficacy. This is the first study to examine such a large library of clinically approved compounds for the identification of novel drug candidates for MCL treatment, the results could be rapidly translated into clinical practice in patients with MCL.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini
Journal: Minor structural modifications to Pracinostat produce big changes in its biological responses. (Pubmed Central) - Aug 20, 2020
It was interesting to find that the corresponding derivative 1 with N-hydroxyacrylamide attached at 5-position was a potent HDAC inhibitor while the others at 6-position were not. This is the first time to demonstrate the position difference plays important role in the HDAC inhibitory activities of the cinnamic hydroxamates.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini
Journal: TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression. (Pubmed Central) - Jul 18, 2020
We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue...Finally, we identified HDAC7 as a key factor whose RNAi-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together these results provide novel mechanistic insight into the essential role HDACs play in TGFβ-mediated fibroblast activation via targeted gene repression.
- |||||||||| pracinostat (SB939) / Helsinn, MEI, Menarini, Mylotarg (gemtuzumab ozogamicin) / UCB, PDL, Pfizer
Trial completion date, Trial primary completion date, Combination therapy: Pracinostat and Gemtuzumab Ozogamicin (PraGO) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - Jul 13, 2020
P1, N=18, Recruiting,
Together these results provide novel mechanistic insight into the essential role HDACs play in TGFβ-mediated fibroblast activation via targeted gene repression. Trial completion date: Mar 2021 --> Mar 2022 | Trial primary completion date: May 2020 --> May 2021
- |||||||||| fenoldopam / Generic mfg., pracinostat (SB939) / Helsinn, MEI, Menarini, fenoterol / Generic mfg.
[VIRTUAL] Epigenetic Regulation of Myofibroblast GPCR Landscape Mediates Antifibrotic Efficacy (ATS 2020 Virtual) - Jul 6, 2020 - Abstract #ATSI2020ATS-I_4938;
Receptor repression impairs the ability to activate antifibrotic downstream signaling. HDAC inhibition provides one means to rescue receptor expression, restoring their availability for exogenous pharmacological targeting or endogenous, disease resolving ligands.
- |||||||||| Jakafi oral (ruxolitinib) / Novartis, Incyte, azacitidine / Generic mfg., danazol oral / Generic mfg.
Review, Journal: Ruxolitinib-based combinations in the treatment of myelofibrosis: worth looking forward to. (Pubmed Central) - Jun 4, 2020
To provide better clinical guidance, comparisons of these randomized controlled trials with the trials of ruxolitinib alone are necessary. This review suggests that the clinical application of ruxolitinib-based combinations is worth waiting for.
- |||||||||| fenoldopam / Generic mfg., pracinostat (SB939) / Helsinn, MEI, Menarini, fenoterol / Generic mfg.
Epigenetic Regulation of Myofibroblast GPCR Landscape Mediates Antifibrotic Efficacy (PENNSYLVANIA CONVENTION CENTER, Hall D-E (200 Level), Area E) - Mar 15, 2020 - Abstract #ATS2020ATS_7465;
Receptor repression impairs the ability to activate antifibrotic downstream signaling. HDAC inhibition provides one means to rescue receptor expression, restoring their availability for exogenous pharmacological targeting or endogenous, disease resolving ligands.
- |||||||||| Review, Journal: Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer. (Pubmed Central) - Feb 6, 2020
Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide...Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression...The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.
- |||||||||| Jakafi oral (ruxolitinib) / Novartis, Incyte, Afinitor (everolimus) / Novartis, decitabine / Generic mfg.
Journal: Overview of the Mutational Landscape in Primary Myelofibrosis and Advances in Novel Therapeutics. (Pubmed Central) - Dec 23, 2019
inhibitors like ruxolitinib, heat shock protein-90 inhibitors like ganetespib, histone deacetylase inhibitors includingpanobinostat, pracinostat, vorinostat and givinostat, hypomethylating agents like decitabine, hedgehog inhibitors likeglasdegib, PI3K, AKT and mTOR inhibitors like everolimus as well as telomerase inhibitors like imtelstat...These include JAKinhibitors like ruxolitinib, heat shock protein-90 inhibitors like ganetespib, histone deacetylase inhibitors includingpanobinostat, pracinostat, vorinostat and givinostat, hypomethylating agents like decitabine, hedgehog inhibitors likeglasdegib, PI3K, AKT and mTOR inhibitors like everolimus as well as telomerase inhibitors like imtelstat. Researchon novel therapeutic options is being actively pursued in order to expand treatment options for primary myelofibrosishowever currently, there is no curative therapy other than allogenic hematopoietic stem cell transplantation (ASCT)which is possible in select patients.
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