nexturastat A / StarWise Therap - LARVOL DELTA

HDAC6 as a Prognostic Factor and Druggable Target in HER2-Positive Breast Cancer. (PubMed, Cancers (Basel)) - "Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance."

Biomarker • Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDC37 • HDAC6 • HER-2 • HSP90AA1

Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer. (PubMed, Nat Cancer) - "Through phase-separation-based screening, we identified Nexturastat A as a specific disruptor of phospho-HDAC6 condensates, which effectively suppresses tumor growth...The phospho-HDAC6-induced aberrant chromatin architecture affects chromatin accessibility, histone acetylation, RNA polymerase II elongation and transcriptional profiles in TNBC. This study demonstrates phospho-HDAC6 LLPS as an emerging mechanism underlying the dysregulation of chromatin architecture in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Development of selective HDAC6 inhibitors to improve cancer immunotherapy (AACR 2024) - "We initially designed in silico 980 compound derivatives from previously reported HDAC6i, such as SS208, Nexturastat A, and Suprastat...Two of these compounds, SM-06-09 and SM-05-947, will be further tested in syngeneic murine melanoma models for their ability in tumor regression and antitumor immunity. This study has yielded important insights into developing new and improved HDAC6is with minimal cytotoxicity, and we believe our work will help advance cancer research and ultimately lead to better patient outcomes."

IO biomarker • Melanoma • Oncology • Solid Tumor • TNFA

Targeting HDAC6 improves anti-CD47 immunotherapy. (PubMed, J Exp Clin Cancer Res) - "Our results demonstrate the critical regulatory role of HDAC6 in phagocytosis and innate immunity for the first time, further underscoring the use of these inhibitors to potentiate CD47 immune checkpoint blockade therapeutic strategies."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Melanoma • Oncology • Solid Tumor • CD47 • SIRPA

HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents. (PubMed, Eur J Med Chem) - "A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • HDAC1 • JAK1 • JAK2 • JAK3

Role of HDAC6-STAT3 in immunomodulatory pathways in Colorectal cancer cells. (PubMed, Mol Immunol) - "We investigated whether HDAC6 inhibitors (HDAC6is), such as Nexturastat A (NextA), affected STAT3 activation in CRC cells. First, we found that NextA is less cytotoxic than the non-selective HDACis panobinostat...These results suggest that treatments with NextA reduce the functionality of STAT3 in CRC cells, impacting the expression of immunomodulatory genes involved in the inflammatory and immune responses. Therefore, targeting HDAC6 may represent an interesting adjuvant strategy in combination with immunotherapy."

Immunomodulating • IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PD-L1 • STAT3

HDAC INHIBITION INVOLVES CD26 EXPRESSION ON MULTIPLE MYELOMA CELLS VIA THE C-MYC/SP1-MEDIATED PROMOTER ACTIVATION AND OVERCOMES THERAPEUTIC RESISTANCE BY HUMANIZED ANTIBODY (EHA 2023) - "Although the cell surface expression of CD26 was relatively low or not detected on 5 myeloma cell lines: KMS11, 26, 27, 28, RPMI8226, cultured alone, an increase in CD26 expression levels was observed within 24 hrs of the treatment with broad inhibitors: panobinistat, vorinostat or isoform-selective inhibitors: romidepsin (HDAC1i), BG45, entinostat, RG2833 (HDAC3i) and nexturastat A, tubastatin A, ricolinostat (HDAC6i) by flow cytometry...First, the expression level of c-Myc in KMS11, 27 and RPMI8226 was time-dependently decreased on treatment with panobinostat or RG2833 both at mRNA and protein levels... HDACi sensitizes myeloma cells with CD26 antigen loss to CD26mAb via c-Myc/Sp1-mediated CD26 induction and augments its cytotoxicity. Molecular markers, Multiple myeloma, MYC, Monoclonal antibody"

Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • DPP4 • HDAC3 • MYC • SDC1

HDAC6 inhibition and HER2 blockade combination overcome Trastuzumab resistance in preclinical models of HER2+ positive breast cancer (EACR 2023) - "NexturastatA antitumor activity was assayed in both WT and HR cells and was effective in reducing cell viability. Furthermore, HDAC6 activity was 15% to 40 % lower in HR subclones as compared to the WT. We finally exposed cells to a combination of low NextA concentrations and Trastuzumab, observing a synergistic effect of the drugs and a reversal of drug resistance in BT474HR subclone.ConclusionOur findings encourage the exploration of the mechanism underlying the effects of HDAC6 inhibition and HER-2 signaling blockade combination."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Inhibition of HDAC6 and HDAC11 has opposite effects on inflammation and the modulation of the functional phenotype of macrophages in the tumor microenvironment (AACR 2023) - " Bone marrow-derived macrophages (BMDMs) isolated from C57BL/6 mice were pre-treated with HDAC6 (NexturastatA) or HDAC11 (FT895) inhibitors prior to polarizing them to M1 and M2 phenotypes...Transcriptomics and single-cell secretome analyses of macrophages indicate that HDAC6 and HDAC11 affects macrophage function in diametrically opposite directions. Therefore, our study underscores the importance of class-selective inhibition of HDACs over pan-HDAC inhibitors and the potential use of selective HDAC inhibitors as a therapeutic option to control macrophage phenotype in cancer and other conditions."

Biomarker • Tumor microenvironment • Melanoma • Oncology • Solid Tumor • CXCL10 • EGF • HDAC11 • HDAC6 • IFNG • IL10 • IL13

Targeting the CD47/SIRPα “Do not eat me” phagocytic pathway in macrophages to improve anti-CD47 immune therapy (AACR 2023) - "We also demonstrated that the combination of systemic administration of the HDAC6 inhibitor Nexturastat A and intertumoral delivery of anti-CD47 reduced SM1 melanoma growth in vivo by increasing immune cell infiltration in the tumor microenvironment. Collectively our results suggest that HDAC6 inhibitors synergize with CD47 blockade to reduce tumor growth and enhance innate antitumor immunity."

IO biomarker • Melanoma • Oncology • Solid Tumor • CD36 • CD47 • GLI2 • LRP1 • SIRPA

Synthesis and biological evaluation of novel N-benzyltriazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors. (PubMed, Bioorg Med Chem) - "In this study, we designed a novel N-benzyltriazolyl-hydroxamate scaffold based on the known HDAC6 inhibitors nexturastat A and tubastatin A. Among the 27 derivatives, 3-fluoro-4-((3-(2-fluorophenyl)-1H-1,2,4-triazol-1-yl)methyl)-N-hydroxybenzamide 4u (HDAC6 IC = 7.08 nM) showed nanomolar HDAC6 inhibitory activity with 42-fold selectivity over HDAC1...Docking analysis revealed that the capping group aligned with the conserved L1 pocket of HDAC6 and was associated with subtype selectivity. Overall, our study explored the triazole-based biaryl capping group and its substitution and orientation, suggesting a rationale for the design of HDAC6-selective inhibitors."

Epigenetic controller • Journal • CNS Disorders • Immunology • Inflammation • Oncology • HDAC1

HDAC Inhibition Involves CD26 Induction on Multiple Myeloma Cells Via the c-Myc/Sp1-Mediated Prompter Activation and Overcomes Therapeutic Resistance By Humanized Antibody (ASH 2022) - "Although the cell surface expression of CD26 was relatively low or not detected on 5 MM cell lines (KMS26, KMS27, KMS28, KMS11, RPMI8226), cultured alone, the increased expression in CD26 levels of MM cells was detectable within 24 hr of the treatment with HDAC1i; FK228, HDAC3i; BG45, MS-275, RG2833 or HDAC6i; nexturastat A, tubastatin A, ACY-1215 as well as broad HDACi; LBH-589, SAHA by flow cytometry... HDACi not only shows anti-MM activity itself but sensitizes MM cells with CD26 antigen loss to CD26mAb via c-Myc/Sp1-mediated CD26 induction and augments its cytotoxicity."

Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • DPP4 • HDAC3 • MYC

Acetylation licenses Th1 cell polarization to constrain Listeria monocytogenes infection. (PubMed, Cell Death Differ) - "Here, through small-molecule screening focusing on epigenetic modifiers during the in vitro Th1 cell differentiation process, we identified that the selective histone deacetylase 6 (HDAC6) inhibitors ricolinostat and nexturastat A (Nex A) promoted Th1 cell differentiation. Stat4 mutant mice lost the ability to normally differentiate into Th1 cells and developed severe Listeria infection. Our study identifies acetylation of STAT4-K667 as an essential signaling event for Th1 cell differentiation and defense against intracellular pathogen infections, and highlights the therapeutic potential of HDAC6 inhibitors for controlling intracellular pathogen infections."

Journal • Infectious Disease • JAK2 • STAT4

Isoform-selective HDAC inhibition up-regulates CD26 expression on multiple myeloma cells and augments cytotoxic efficacy by humanized monoclonal antibody (AACR 2022) - "Although the cell surface expression of CD26 was relatively low or not detected on 5 MM cell lines (KMS26, KMS27, KMS28, KMS11, RPMI8226), the increased expression in CD26 levels was detectable within 24 h of the treatment with HDAC1i; FK228, HDAC3i; BG45, MS-275, RG2833 or HDAC6i; nexturastat A, tubastatin A, ACY-1215 as well as broad HDACi; LBH-589, SAHA... Combination with isoform-selective HDACi not only shows anti-MM activity but supports as immunopotentiators by sensitizing CD26neg MM cells to CD26mAb and augment its cytotoxicity against MM cells."

Clinical • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • DPP4 • HDAC1 • HDAC3

Effect of HDAC6 inhibition on the expression of immunomodulator genes in colorectal cancer cells (AACR 2022) - "Here, we investigate whether HDAC6 affects STAT3 activation in CRC cells, through treatments with Nexturastat A (NextA), a specific HDAC6 inhibitor, that indirectly, decreases the levels of activating post-translational modifications on STAT3 analyzed by Western blot and flow cytometry...These results suggest that treatments with specific HDAC6 inhibitors would reduce the functionality of STAT3 in CRC cells, impacting the expression of immunomodulator genes involved in the immune response, as IL-10, PD-L1 and others. Therefore, the use of specific HDAC6 inhibitors may be a reasonable and an interesting adjuvant strategy for help in checkpoint inhibitors immunotherapy, since HDAC6 inhibitors would indirectly decrease PD-L1 expression, one of the checkpoint inhibitors of immune system."

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • IL10 • IL6 • PD-1 • STAT3

Small-molecule compounds boost genome-editing efficiency of cytosine base editor. (PubMed, Nucleic Acids Res) - "Our study provides a new strategy to improve the activity and specificity of CBE in human cells. Ricolinostat and Nexturastat A augment the effectiveness and applicability of CBE."

Journal • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Oxa analogues of nexturastat A demonstrate improved HDAC6 selectivity and superior anti-leukaemia activity. (PubMed, ChemMedChem) - "During our lead structure identification, we demonstrated that a hydroxylamine subunit proves to be beneficial for HDAC6 selectivity and established the synthesis of N -alkoxyurea based hydroxamic acids 4. Here we report highly potent N -alkoxyurea based hydroxamic acids with improved HDAC6 preference compared to nexturastat A. We further validated the biological activity of these oxa analogues of nexturastat A in a broad subset of leukaemia cell lines and demonstrated their superior anti-proliferative properties compared to nexturastat A."

Journal • CNS Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology

Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells. (PubMed, Sci Rep) - "In this study, we evaluated the HDAC6i Nexturastat A as a priming agent to facilitate the transition of the tumor microenvironment from "cold" to "hot", and potentially augment immune check-point blockade therapies...The evaluation of individual components of the tumor microenvironment suggested that the in vivo anti-tumor activity of HDAC6i is mediated by its effect on tumor cells and tumor-associated macrophages, and not directly over T cells. Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically "cold" tumors and subsequently improve ongoing immune check-point blockade therapies."

Checkpoint inhibition • Journal • Immune Modulation • Inflammation • Melanoma • Oncology • Solid Tumor

Design, Synthesis and Evaluation of Novel Indirubin-based N-Hydroxybenzamides, N-Hydroxypropenamides and N-Hydroxyheptanamides as Histone Deacetylase Inhibitors and Antitumor Agents. (PubMed, Bioorg Med Chem Lett) - "Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat)...The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA...Docking studies revealed some important features affecting the selectivity against HDAC6 isoform. The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development."

Journal • Oncology • HDAC2

Development of Multi-Functional Histone Deacetylase 6 Degraders with Potent Anti-Myeloma Activity. (PubMed, J Med Chem) - "We herein report our new generation of multifunctional HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat A with CRBN ligand that can synergize with HDAC6 degradation for the antiproliferation of multiple myeloma (MM). This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC50 and promising anti-proliferation activity in multiple myeloma (MM) cells."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation

Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy)methyl)-N-hydroxybenzamides / propenamides as Histone Deacetylase Inhibitors and Antitumor Agents. (PubMed, Anticancer Agents Med Chem) - "Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101)...Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer)...Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity...These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities."

Journal

The selective HDAC6 inhibitor Nexturastat A induces apoptosis, overcomes drug resistance and inhibits tumor growth in multiple myeloma. (PubMed, Biosci Rep) - "Additionally, NexA could overcome bortezomib (BTZ) resistance in MM cells, and NexA in combination with BTZ had stronger efficacy. We also confirmed that NexA inhibited tumor growth in murine xenograft models of MM. These interesting findings provided the rationale for the future advancement of this novel HDAC6 inhibitor as a potential therapeutic anti-myeloma agent."

Journal

Class I-Histone Deacetylase (HDAC) Inhibition is Superior to pan-HDAC Inhibition in Modulating Cisplatin Potency in High Grade Serous Ovarian Cancer Cell Lines. (PubMed, Int J Mol Sci) - "Four HGSOC cell lines with different cisplatin sensitivity were treated with combinations of cisplatin and entinostat (class I HDACi), panobinostat (pan-HDACi), or nexturastat A (class IIb HDACi), respectively. The effect of HDAC inhibitors could be attributed to the upregulation of pro-apoptotic genes (CDNK1A, APAF1, PUMA, BAK1) and downregulation of survivin. In conclusion, the combination of entinostat and cisplatin is synergistic in HGSOC and could be an effective strategy for the treatment of aggressive ovarian cancer."

Journal • Preclinical

Indocyanine Green-Nexturastat A-PLGA Nanoparticles Combine Photothermal and Epigenetic Therapy for Melanoma. (PubMed, Nanomaterials (Basel)) - "These advantages persisted in vivo in a syngeneic murine model of melanoma, where the combination therapy slowed tumor progression and improved median survival. These findings demonstrate the potential of INAPs as agents of PTT and epigenetic therapy for melanoma."

Journal

Priming the tumor microenvironment with epigenetic modifiers to overcome resistance to immune checkpoint inhibitors (AACR 2019) - "...In this study, we evaluated the immunological modulation of the HDAC6i Nexturastat A in combination with anti-PD-1 checkpoint blockade therapy and the use of this HDAC6i as a priming agent to facilitate the transition of the tumor microenvironment from “cold” to “hot” in order to more specifically augment immune check-point blockade therapies...The evaluation of the effect of HDAC6i on individual immune components suggest that the in vivo anti-tumor activity of HDAC6i is mediated by its effect on tumor cells and tumor associated macrophages, and not directly over T cells. Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically “cold” tumors and subsequently improve ongoing immune check-point blockade therapies."

Biomarker • Checkpoint inhibition • Late-breaking abstract • Tumor microenvironment