- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal, Epigenetic controller: Class Ⅰ histone deacetylase inhibitor regulate of Mycobacteria-Driven guanylate-binding protein 1 gene expression. (Pubmed Central) - Aug 11, 2022
Class Ⅰ histone deacetylase inhibitor (HDACi) MS-275 can selectively inhibit GBP1 expression, ultimately affecting the release of inflammatory cytokines IL-1β and suppressing Mtb intracellular survival...Besides, using the bisulfite sequencing PCR, we showed that the CpG site of the GBP1 promoter was hypermethylated, and the methylation status of the GBP1 promoter did not change significantly upon Mtb infection. Overall, this study sheds light on the role of GBP in Mtb infection and provides a link between epigenetics and GBP1 activity.
- |||||||||| Jingzhuda (entinostat) / EOC Pharma, EddingPharm, Opdivo (nivolumab) / BMS
Enrollment closed, Trial completion date, Trial primary completion date, Metastases: Phase II Anti-PD1 Epigenetic Therapy Study in NSCLC. (clinicaltrials.gov) - Aug 3, 2022
P2, N=101, Active, not recruiting,
Conclusions Clinical data and CRC cell-line or primary tissue cultures identify SG formation as a resistance factor for chemotherapy and as a therapeutic target in CRC. Recruiting --> Active, not recruiting | Trial completion date: Aug 2022 --> Aug 2024 | Trial primary completion date: Aug 2022 --> Aug 2023
- |||||||||| Epidaza (chidamide) / Chipscreen, Meiji Seika, Eisai, HUYA Bioscience, entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal: High-Throughput Identification of Epigenetic Compounds to Enhance Chicken Host Defense Peptide Gene Expression. (Pubmed Central) - Jul 29, 2022
Moreover, oral gavage of entinostat significantly enhanced HDP gene expression in the chicken intestinal tract. Collectively, the high throughput assay proves to be effective in identifying HDP inducers, and both entinostat and tucidinostat could be potentially useful as alternatives to antibiotics to enhance intestinal immunity and disease resistance.
- |||||||||| gemcitabine / Generic mfg.
Journal: Synergistic Antitumoral Effect of Epigenetic Inhibitors and Gemcitabine in Pancreatic Cancer Cells. (Pubmed Central) - Jul 29, 2022
The combination of UVI5008 or MS275 with gemcitabine induced a synergistic effect at low concentration and the RNA-Seq analysis revealed some synergy candidate genes as potential biomarkers. Reverting aberrant epigenetic modifications in combination with gemcitabine offers an alternative treatment for PDAC patients, with an important reduction of the therapeutic dose.
- |||||||||| molibresib (GSK525762) / GSK, entinostat (SNDX-275) / Syndax Pharma, EOC Pharma, Zejula (niraparib) / GSK, J&J, Takeda
Hypomethylating agents synergistically combine with PARP inhibitors in ovarian cancer (Poster Area, Hall 4) - Jul 28, 2022 - Abstract #ESMO2022ESMO_2316;
Detailed mean CI values will be reported as well as RNAseq data on the effects of each epigenetic drug across all 10 OC lines. Conclusions Consistent synergistic interactions of niraparib plus 5-aza-2'deoxycytidine across a wide range of clinically relevant concentrations in ovarian cancer cells indicate that it is a rational combination to test and prioritize in human clinical trials.
- |||||||||| entinostat (SNDX-275) / Syndax Pharma, EOC Pharma, Opdivo (nivolumab) / Ono Pharma, BMS, Yervoy (ipilimumab) / Ono Pharma, BMS
Monitoring immune checkpoint inhibition in advanced solid tumors using genome-wide cfDNA fragmentomes (Poster Area, Hall 4) - Jul 28, 2022 - Abstract #ESMO2022ESMO_2013;
P1
Conclusions There is a clinical need for non-invasive tests to identify primary or acquired resistance to ICIs, sparing patients from ineffective treatments associated with immune-related adverse events. Here, we demonstrate a cfDNA fragmentation based approach for molecular detection of disease progression that could guide future trials with ICIs.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal: Dynamic profiling and functional interpretation of histone Kcr and Kla during neural development. (Pubmed Central) - Jul 24, 2022
Using P19 cells as induced neural differentiation system, we find that HDAC1-3 inhibition by MS-275 pre-activates neuronal transcriptional programs through stimulating multiple histone lysine acylations simultaneously. These findings suggest histone Kcr and Kla play critical roles in the epigenetic regulation of neural development.
- |||||||||| JQ-1 / Roche, GSK1324726A / GSK, entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal, PD(L)-1 Biomarker, IO biomarker: Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma. (Pubmed Central) - Jul 6, 2022
Cultured B16F10 cells and human UM cells were treated with the histone deacetylase inhibitor (HDACi) entinostat or BETi JQ1...Co-treatment with the bioavailable BETi iBET726 impaired the immunotherapy effect...Indeed, co-cultures of UM with HLA-matched melanoma-specific tumor-infiltrating lymphocytes (TILs) resulted in higher TIL-mediated melanoma killing when entinostat was added. Further exploration of combined immunotherapy and epigenetic therapy in metastatic melanoma resistant to PD-1 inhibition is warranted.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Biomarker, Journal, Tumor Mutational Burden, PD(L)-1 Biomarker, IO biomarker: Tumor-targeted interleukin-12 synergizes with entinostat to overcome PD-1/PD-L1 blockade-resistant tumors harboring MHC-I and APM deficiencies. (Pubmed Central) - Jul 6, 2022
Further exploration of combined immunotherapy and epigenetic therapy in metastatic melanoma resistant to PD-1 inhibition is warranted. Our findings provide a rationale for combining the tumor-targeting NHS-IL12 with the histone deacetylase inhibitor entinostat in the clinical setting for patients unresponsive to αPD-1/αPD-L1 and/or with innate deficiencies in tumor MHC-I, APM expression, and IFN-γ signaling.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), Jingzhuda (entinostat) / EOC Pharma, EddingPharm
Trial completion date, Trial primary completion date, Combination therapy, Epigenetic controller: Testing the Safety and Efficacy of the Combination of the Antibody Pembrolizumab and Entinostat in Patients With Myelodysplastic Syndrome Who Are Not Responding to Hypomethylating Agents (clinicaltrials.gov) - Jul 5, 2022
P1b, N=27, Active, not recruiting,
Our findings provide a rationale for combining the tumor-targeting NHS-IL12 with the histone deacetylase inhibitor entinostat in the clinical setting for patients unresponsive to αPD-1/αPD-L1 and/or with innate deficiencies in tumor MHC-I, APM expression, and IFN-γ signaling. Trial completion date: Jun 2022 --> Jun 2023 | Trial primary completion date: Jun 2022 --> Jun 2023
- |||||||||| ZEN-3694 / Zenith Capital Corp, Jingzhuda (entinostat) / EOC Pharma, EddingPharm
Enrollment open, Trial completion date, Trial primary completion date, Metastases: Testing A New Anti-cancer Drug Combination, Entinostat and ZEN003694, for Advanced and Refractory Solid Tumors and Lymphomas (clinicaltrials.gov) - Jun 30, 2022
P1/2, N=30, Recruiting,
Trial completion date: Jun 2022 --> Jun 2023 | Trial primary completion date: Jun 2022 --> Jun 2023 Not yet recruiting --> Recruiting | Trial completion date: May 2023 --> Jul 2025 | Trial primary completion date: May 2023 --> Jul 2025
- |||||||||| Regulation of chromatin epigenetic modification by the nucleosomal kinase VRK1; implications for new cancer therapies (Poster Area) - Jun 28, 2022 - Abstract #EACR2022EACR_1072;
HDAC (Vorinostat, Entinostat, Panobinostat, Selisistat, Thiomyristoil, AGK2; and AK7) and KMT (Chaetocin and Tazemetostat) inhibitors mimic the effect of VRK1 on histone marks...Conclusion Our findings revealed that permissive chromatin marks decreased (H3K4me3; H3K9ac, H3K27ac, H4K16ac) while repressive marks (H3K9me3; H3K27me3) increased in VRK1-depleted cells. Therefore, the loss of VRK1 expression in the cells had the same effect than the inhibition of these enzymes, suggesting that VRK1 might be a regulator of those epigenetic enzymes and used as new target in synthetic lethality strategies.
- |||||||||| Jingzhuda (entinostat) / EOC Pharma, EddingPharm
Trial completion date, Trial primary completion date, Combination therapy, Mismatch repair: ENCORE 601: Ph1b/2 Dose-Escalation Study of Entinostat With Pembrolizumab in NSCLC With Expansion Cohorts in NSCLC, Melanoma, and Colorectal Cancer (clinicaltrials.gov) - Jun 22, 2022
P1b/2, N=202, Active, not recruiting,
Future studies may focus on the clinical difference among different HDACi and AE managements to enhance tolerability. Trial completion date: Jun 2022 --> Sep 2022 | Trial primary completion date: Jun 2022 --> Sep 2022
- |||||||||| Zolinza (vorinostat) / Merck (MSD), entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma, Istodax (romidepsin) / Astellas, BMS
Journal: Current paradigms in epigenetic anticancer therapeutics and future challenges. (Pubmed Central) - Jun 19, 2022
Moreover, the alterations seen in tumors are not well understood for which one has to gain deeper insight into the tumor pathology as well. Current review focusses on such epigenetic alterations occurring in cancer and the effective strategies to utilize such alterations for potential therapeutic use and treatment in cancer.
- |||||||||| Zolinza (vorinostat) / Merck (MSD), entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Preclinical, Journal, Epigenetic controller: A novel aromatic amide derivative SY-65 co-targeted tubulin and histone deacetylase 1 with potent anticancer activity in vitro and in vivo. (Pubmed Central) - Jun 15, 2022
Especially, compound SY-65 exhibited potent antiproliferative activity against MGC-803, HGC-27 and SGC-7901 cells with IC values <55 nM, which was better than that of Colchicine, MS-275 and SAHA...Compound SY-65 also exhibited a good tumor inhibitory effect in vivo without obvious toxicity. Therefore, compound SY-65 could be developed as a novel tubulin/HDAC1 candidate inhibitor for future cancer therapeutics.
- |||||||||| Jingzhuda (entinostat) / EOC Pharma, EddingPharm
Biomarker, Enrollment change, Trial termination: A Phase I, Multicenter, Open Label Study on the Effects of SNDX-275 on Expression of Biomarkers in Subjects With Newly Diagnosed Breast Cancer (clinicaltrials.gov) - Jun 6, 2022
P1, N=1, Terminated,
To the best of our knowledge, this is the first report to compare the enzymatic profile of three promising ZBGs of HDAC inhibitors. N=30 --> 1 | Withdrawn --> Terminated
- |||||||||| Jingzhuda (entinostat) / EOC Pharma, EddingPharm
Trial completion date, Trial primary completion date, Combination therapy, Mismatch repair: ENCORE 601: Ph1b/2 Dose-Escalation Study of Entinostat With Pembrolizumab in NSCLC With Expansion Cohorts in NSCLC, Melanoma, and Colorectal Cancer (clinicaltrials.gov) - May 26, 2022
P1b/2, N=202, Active, not recruiting,
In conclusion, we demonstrate that inhibition of specific HDACs is a potential means to enhance OAd activity, supporting clinical translation. Trial completion date: Aug 2019 --> Jun 2022 | Trial primary completion date: Aug 2019 --> Jun 2022
- |||||||||| Zolinza (vorinostat) / Merck (MSD), entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal: Development of New Inhibitors of HDAC1-3 Enzymes Aided by In Silico Design Strategies. (Pubmed Central) - May 26, 2022
The designed compounds 3a and 3b showed 65-80 and 5% inhibition on HDAC 1, 2, and 3 isoforms at a concentration of 10 μM, respectively. The novel compound 3a may be used as a lead structure for designing new HDAC inhibitors.
- |||||||||| RGFP966 / BioMarin, entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal: Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity. (Pubmed Central) - May 20, 2022
In addition, we show that RGFP966, commercialized as an HDAC3-selective probe, is a slow-binding inhibitor with inhibitor constants of 57, 31, and 13 nM against HDACs 1-3, respectively. These data highlight the need for thorough kinetic investigation in the development of selective HDAC probes.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal: HDAC1 inhibition promotes pathogenic Th17 cell expansion in the context of high salt. (Pubmed Central) - May 14, 2022
Conditioned media included physiologic Th17 (TGFb1, IL-6, anti-IFNg, anti-IL-4, anti-CD28) and pathogenic Th17(23) (IL-1b, IL-23, IL-6, anti-IFNg, anti-IL-4, anti-CD28) cytokines with or without high sodium (40 mM NaCl) or MS-275, an HDAC1 inhibitor (300 nM) in the media...These data indicate that NaCl-responsive IL-23R dependent signaling is regulated in part by HDAC1. Further investigation is necessary to understand the in vivo effects of high sodium intake on HDAC1 activity.
- |||||||||| Zolinza (vorinostat) / Merck (MSD), Tomudex (raltitrexed) / Pfizer, AstraZeneca, entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Journal, Combination therapy: Effect of Uracil DNA Glycosylase Activity on the Efficacy of Thymidylate Synthase Inhibitor/HDAC Inhibitor Combination Therapies in Colon Cancer. (Pubmed Central) - May 14, 2022
Interestingly, UNG2 protein levels can also be depleted by the HDAC inhibitors SAHA and MS275, providing a pharmacologic strategy to reduce UNG2 activity in cells...Our combined genetic and pharmacologic strategies targeting UNG2 activity in cells are defining cell death mechanisms for combination therapies of TS inhibitors and HDAC inhibitors. Future work will examine these drug combinations in additional cell lines to understand optimal therapeutic combinations and to further refine mechanisms of cell death.
- |||||||||| Journal, PARP Biomarker: Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures. (Pubmed Central) - May 12, 2022
Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, and 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, and high-dose zoledronic acid)...Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2a inhibitors, temozolomide, dabrafenib, or octreotide...Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma, Tazverik (tazemetostat) / Epizyme, Eisai
Impact of epigenetic regulators on CD1d expression in Ewing’s sarcoma cell lines () - May 9, 2022 - Abstract #CIMT2022CIMT_248;
Our data suggest that epigenetic regulators induce CD1d expression in ES cell lines. Further studies are needed whether the induction of CD1d expression in ES cells may enhance the cytotoxic efficiency of unconventional T cells, and therefore offers new treatment options for patients diagnosed with ES.
- |||||||||| axatilimab (SNDX-6352) / Syndax Pharma, Incyte
Trial completion, Combination therapy, Monotherapy, Metastases: A Phase 1 Study to Investigate SNDX-6352 Alone or in Combination With Durvalumab in Patients With Solid Tumors (clinicaltrials.gov) - May 6, 2022
P1, N=45, Completed,
Further studies are needed whether the induction of CD1d expression in ES cells may enhance the cytotoxic efficiency of unconventional T cells, and therefore offers new treatment options for patients diagnosed with ES. Active, not recruiting --> Completed
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
Biomarker, Journal, Tumor microenvironment: Entinostat decreases immune suppression to promote anti-tumor responses in a HER2+ breast tumor microenvironment. (Pubmed Central) - May 6, 2022
Overall, our in-depth analysis suggests that entinostat-induced changes on multiple myeloid cell types reduce immunosuppression and increase anti-tumor responses, which, in turn, improve sensitivity to ICIs. Sensitization of the TME by entinostat could ultimately broaden the population of patients with breast cancer who could benefit from ICIs.
- |||||||||| SNDX-5613 / Syndax Pharma, ziftomenib (KO-539) / Kura Oncology
Review, Journal: Menin-MLL protein-protein interaction inhibitors: a patent review (2014-2021). (Pubmed Central) - May 6, 2022
In addition, they are undergoing clinical evaluation for other indications. It is clear that Menin-MLL interaction inhibitors have promising benefits in the clinical treatment of leukemia and other diseases.
- |||||||||| entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma, Tecentriq (atezolizumab) / Roche
Phase I study of entinostat (Ent), atezolizumab (A), carboplatin (C), and etoposide (E) in previously untreated extensive-stage small cell lung cancer (ES-SCLC), ETCTN 10399. () - Apr 28, 2022 - Abstract #ASCO2022ASCO_5741;
P1
The combination of low dose Ent 2 mg PO weekly + AC-E is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia in the first 1-2 weeks and ≥Gr 3 neutropenia and thrombocytopenia prior to completing 2 cycles of treatment for all pts. There is no role for further exploration of entinostat with carboplatin, etoposide, and atezolizumab.
- |||||||||| Zolinza (vorinostat) / Merck (MSD), entinostat (SNDX-275) / Kyowa Kirin, Syndax Pharma
EPIGENETIC MASTER REGULATORS HDAC1 AND HDAC5 CONTROL PATHOBIONT ENTEROBACTERIA COLONIZATION IN ILEAL MUCOSA OF CROHN'S DISEASE PATIENTS (Poster Hall - San Diego Convention Center) - Apr 25, 2022 - Abstract #DDW2022DDW_4791;
Transgenic mice expressing human CEACAM6 treated with a class I HDAC inhibitor (MS-275) or HDAC5 inhibitor (LMK-235) were orally challenged with the AIEC strain LF82 and AIEC intestinal colonization was followed up by numbering AIEC bacteria in the stools and associated to colonic mucosa...HDAC1 and HDAC5 expression levels are misregulated in CD patients, which favors Enterobacteria encroachment. These data are of interest to better understand the molecular mechanisms leading to AIEC colonization in CD patients and to bring to light new therapeutic targets.
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