rocilinostat (ACY-1215)

In summary, ACY1215 can inhibit the NF-κB and STAT3 signaling pathways in astrocytes, reduce inflammation and ameliorate SCI. Our results provide a novel strategy for the treatment of SCI.

P1/2, N=23, Terminated, Jennifer Amengual | Completed --> Terminated; Lack of funding

P1/2, N=103, Terminated, Celgene | Active, not recruiting --> Terminated; Lack of efficacy

ACY-1215 has a protective effect on the cellular model of NAFLD induced by fatty acids and lipopolysaccharide, as well as the C57BL/6J mouse model induced by a high-fat diet. ACY-1215 may play a protective role by inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway.

P1, N=3, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Apr 2024 --> Apr 2026

Fab' fragments from Obinutuzumab (OBN) and Isatuximab (ISA) were employed in the synthesis of anti-CD20 (Fab'OBN-MORF1) and anti-CD38 (Fab'ISA-MORF1) bispecific engagers...Pretreatment of patient cells with gemcitabine or ricolinostat markedly increased cell surface CD20 and CD38 expression, respectively...Our findings demonstrate DFMT's potential in personalized CLL therapy. Further research is needed to validate these outcomes in a larger number of patient samples and to explore DFMT's applicability to other malignancies.

This study reveals a novel regulatory mechanism of HDAC6 on non-histone substrates, especially on protein acetylation. HDAC6 inhibitors may be of great significance in tumor immunotherapy and related combination strategies.

P1/2, N=103, Active, not recruiting, Celgene | Phase classification: P1b/2 --> P1/2 | Trial completion date: Jun 2023 --> Jan 2024 | Trial primary completion date: Jun 2023 --> Jan 2024

P1, N=10, Completed, Beijing 3E-Regenacy Pharmaceuticals Co., Ltd. | Recruiting --> Completed | N=57 --> 10 | Trial completion date: Apr 2024 --> Nov 2023

The HTS revealed that the histone deacetylase 6 (HDAC6)-selective inhibitors tubastatin-A, ACY-738 and ACY-1215 increased proteasome activity in a panel of multiple myeloma (MM) cell lines. Proteasome activators also represent a paradigm-shifting approach to overcome mechanisms of immune escape. FDA-approved drugs that increase proteasome activity and boost antigen presentation can now be repositioned as cancer immunotherapeutics to overcome the existing bottlenecks in drug development.

In vitro, (1S, 3R)-1-(4-chlorophenyl)-N-(4-(hydroxycarbamoyl)benzyl)-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxamide (14g) showed potent broad antiproliferative activity against various tumors including leukemia, colon cancer, melanoma, and breast cancer cell lines, better than ACY-1215. Moreover, 14g also showed good pharmacokinetics properties in mice via oral administration.

2) Meticrane showed additive/synergistic effects with epigenetic inhibitors (DNMT1/5AC, HDACs/CUDC-101 and HDAC6/ACY1215). Beyond that, we have expressed some concerns confronted during testing meticrane that also apply to other non-oncology drugs when considered for future clinical or preclinical purposes. Taken together, meticrane is involved in some anticancer pathways that are passively targeting cancer cells and may be considered as compatible with epigenetic inhibitors.

Exploring the differential metabolism of KL and KP mutant NSCLC, we identified decreased metabolic reserve in KL mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC based on a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.

Thus, we designed a phase 1b dose-escalation clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in patients with metastatic BC (MBC) (NCT02632071). Analysis of other tumor types also identified multiple cohorts with predicted sensitivity to HDAC6i's. Mechanistically, we have linked the anticancer activity of HDAC6i's to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells.

In conclusion, our study showed that ricolinostat suppressed proliferation by inducing G2/M phase arrest and promoted apoptosis in cervical cancer cells, indicating that ricolinostat may be a promising antitumor agent in cervical cancer. Also, ricolinostat and topotecan/etoposide combination are synergistic in cervical cancer cells.

Besides, our results also proved that ACY-1215 can synergize with imatinib to suppress chronic myeloid leukemia in vitro and in vivo. On the whole, our study revealed that HDAC6 is a possible therapeutic target in CML, and the combination therapy of TKI and HDAC6 inhibitor may improve the outcome of CML patients.

Our data demonstrated that the co‑administration of RCS with Adv in HNSCC cells resulted in the suppression of Chk1 activity, leading to synergistically enhanced apoptosis via mitotic catastrophe in a p53‑dependent manner. This enhanced cell death appeared to be partially mediated by the inhibition of HDAC6 activity by RCS.

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.

In agreement, pharmacological inhibition of MITF signaling with ML329 significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and reduced OMM2.5 cells in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of OMM2.5 MUM cells.

Next, we demonstrated that inhibition of HDAC6 function, using the HDAC6-specific inhibitor ACY1215 or by transfection with HDAC6 short hairpin RNA (shRNA), can reverse the migratory and invasive phenotype of ARID1A-knockdown cells. Further, we also show that inhibition of HDAC6 activity causes an apoptotic vulnerability to etoposide treatments in ARID1A-deficient cells. In summary, the findings exposed in this work indicate that inhibition of HDAC6 activity is a potential therapeutic strategy for patients suffering from ARID1A-mutant endometrial cancer diagnosed in advanced stages.

Increase in GRP78 acetylation by HDAC6 inhibition suppressed GRP78 translocation to the cell surface, which inhibited proliferation and promoted apoptosis in CCA.

More importantly, it was observed that combination of ACY‑1215 and ATM inhibitors exhibited markedly more potent antitumor activity than the individual compound in xenograft mouse models of breast cancer with mutant p53. Collectively, our results demonstrated that ACY‑1215 is a novel chemotherapeutic agent that could restore mutant p53 function in cancer cells with strong antitumor activity, either alone or in combination with inhibitors of the ATM protein kinase.

49 induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). Additionally, 61 was well tolerated in an in vivo zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.

The ROS scavenger, N-acetyl cysteine, abrogated the increase in cytotoxicity. These results suggest the potential therapeutic value of the dual targeting of the proteasome and HDCA6 for head and neck cancers through the induction of necroptosis-like cell death along with ROS generation.

We found that HDAC6 inhibitors ACY-1215 (1215) and ACY-738 (738) inhibited the proliferation of multiple patient-derived and mouse glioma cells. Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of glioma cells through primary cilia.

Based on these results, we designed a phase Ib clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in metastatic BC patients. Expansion of our analysis to other tumor types identified multiple cohorts enriched in high HDAC6 score samples. These results suggest that the HDAC6 score may provide an effective, CLIA certified predictive biomarker of ricolinostat sensitivity in multiple human cancers.

Significantly, we found that tektin4 loss sensitized TNBC cells, xenograft models, and patient-derived organoid models to the HDAC6-selective inhibitor ACY1215. Furthermore, tektin4 expression levels were positively correlated with microtubule stability levels in clinical samples. Together, our findings uncover a metastasis suppressor function of tektin4 and support clinical development of HDAC6 inhibition as a new therapeutic strategy for tektin4-deficient TNBC patients.

We therefore investigated the potential of the histone deacetylase (HDAC) inhibitor ricolinostat to up-regulate CD38 on MM cells, thereby enhancing the performance of CD38-specific therapies. We also evaluated next-generation HDAC6 inhibitors (ACY-241, WT-161) and observed similar increase of CD38 levels suggesting that the upregulation of CD38 expression on MM cells by HDAC6 inhibitors is a class effect. This proof-of-concept illustrates the potential benefit of combining HDAC6 inhibitors and CD38-directed immunotherapy for MM treatment.

The HDAC6 inhibitor ACY1215 increases the chemotherapy effect of gemcitabine and oxaliplatin. ACY1215 could suppress cell proliferation and induce apoptosis of GBC-SD and SGC-996, and increased the chemotherapy effect of gemcitabine and oxaliplatin, which provides a rationale for the combination of HDAC6 selective inhibitors with other anticancer agents in treating gallbladder cancer.

P1, N=17, Completed, Columbia University | Active, not recruiting --> Completed | Trial completion date: Jan 2020 --> Sep 2020 | Trial primary completion date: Oct 2019 --> Sep 2020

When a taxane was used in combination with AZD6244 and ACY1215 by a simultaneous schedule, a synergistic cytotoxic effect together with increased apoptosis was evidenced in all cell models. These results support a rational use of targeted agents to improve prostate cancer cell apoptotic response.

JBI-802 had a much stronger effect in inhibiting the growth of HEL92.1.7 erythroleukemia xenograft by oral administration when compared to ACY-1215, a HDAC6 selective inhibitor or ORY-1001 an LSD1 selective inhibitor. The data obtained to date demonstrate that dual LSD1-HDAC6/8 inhibitors could serve as novel, effective therapeutic agents for treatment of select subset of AML and other cancers. IND-enabling studies are in progress with this inhibitor to be developed as a clinical candidate

Ricolinostat 240 mg qd is safe and tolerable with weekly nab-paclitaxel. Clinical activity has been observed, with the majority of patients demonstrating SD and 1 with a PR. High HDAC6-score associates with longer PFS and should be evaluated in larger trials as a predictor of response to HDAC6 inhibition.

HDAC6-selective inhibitors augmented melanoma patient T-cell immune properties, providing a rationale for translational investigation assessing their potential clinical efficacy.

HDAC6 was inhibited with small molecule inhibitors tubacin and ACY1215 in vitro and in vivo...Our data show that HDAC6 in NSCLC cells supports Notch1 signaling and promotes cell survival and proliferation. Our results support clinical investigation of HDAC6 inhibitors as a potential therapeutic option for treatment of NSCLC patients.

Lenalidomide (Len) selectively binds to cereblon (CRBN), which mediates recruitment of specific substrates like IKZF1 to E3 ubiquitin ligase and subsequent degradation, resulting in downregulation of IRF-4 and c-Myc...We observed that ADCC activity of both daratumumab and elotuzumab against MM cells was enhanced in the presence of HDAC inhibitors, which was compatible with our previous data that HDAC inhibitors upregulated MICA mRNA expression via inhibition of IKZF1 (ASH2018 abstract #4435)...Afuresertib, an AKT inhibitor, suppressed GSK-3 phosphorylation (p-GSK-3) with or without ACY-1215, an HDAC inhibitor, leading to a substantial decrease of c-Myc (Figure 2)...Bortezomib, doxorubicin, and dexamethasone resistant MM cell lines were also sensitive to CUDC-907...Furthermore, CUDC-907 was effective on primary MM cells which were resistant to bortezomib and Len (Figure 5). Thus, dual inhibition of HDAC and AKT with or without monoclonal antibodies is a promising therapeutic approach to multi-drug resistant MM.