HDAC Inhibition Triggers Release of RNA Polymerase II from Promoter-Proximal Pausing in Healthy Blood Progenitors and Primary Acute Myeloid Leukemia Myeloblasts

Article

作者: Xing, Yanzi ; Mannervik, Mattias ; Ax, Kajsa ; Lehmann, Sören ; Hunt, George ; Pfab, Alexander ; Ungerstedt, Johanna

Abstract:

Histone deacetylase (HDAC) inhibitors have been considered as anti-leukemic agents but have shown poor efficacy in clinical trials. In this study, we investigated the immediate transcriptional response to the HDAC inhibitor SAHA (vorinostat) in healthy CD34+ blood stem/progenitor cells and myeloblasts from patients with primary acute myeloid leukemia (AML) carrying TET2 and NPM1 mutations. We found that although healthy CD34+ and AML cells differed substantially at the transcriptional level, they responded very similarly to 10-minute SAHA treatment. HDAC inhibition led to a global increase in histone acetylation; however, only 150 to 250 genes were upregulated. These were involved in oxidative stress, metabolism, chromatin regulation, cell cycle control, and cell death, and the vast majority was upregulated in both healthy and AML cells. Upregulated genes were more highly acetylated compared with average expressed genes and had higher levels of promoter-proximal paused RNA polymerase II (Pol II) before treatment. Upon HDAC inhibition, upregulated genes increased BRD4 occupancy the most and released paused Pol II into transcription elongation. Our results suggest that the immediate effect of HDAC inhibition is to trigger release of paused Pol II into elongation. We speculate that the similar transcriptional response in healthy and leukemic cells may contribute to the poor efficacy of HDAC inhibitors in patients with hematologic malignancies.

2026-02-01·CURRENT PHARMACEUTICAL DESIGN

New Standards in the Treatment of Advanced Metastatic Melanoma: Immunotherapy and BRAF-Targeted Therapies as Emerging Paradigms

Review

作者: Kreidieh, Firas ; Wong, Michael K.

Although cutaneous melanoma accounts for only about 2% of skin cancers, its rapid progression makes it an aggressive skin cancer with a high mortality rate. As of 2018, the SEER database estimated that the 5-year overall survival (OS) rate is 29.8% in patients with stage IV disease at diagnosis in the United States. Non-cutaneous melanoma, including mucosal and uveal subtypes, carries a generally worse prognosis. Once considered refractory to conventional treatments, such as chemotherapy and radiation therapy, the advent of immunotherapy, including immune checkpoint inhibitors (ICIs), vaccines, and tumor-infiltrating lymphocytes (TIL), and of targeted therapy over the past decade has resulted in dramatic improvements in melanoma. Importantly, ICIs have resulted in long-term remission for patients with melanoma, thus introducing the possibility of a cure for some patients with metastatic disease. These include antibodies against programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3). In this review, we will provide an overview of metastatic melanoma while focusing on its current pharmacologic armamentarium, toxicities of treatment, including ICIs and targeted therapy, and its therapeutic clinical strategies. The therapeutic advances presented in this review serve as the foundation for an ever-expanding repertoire of innovative approaches. These include mRNA vaccines, oncolytic viruses, bispecific engagers, oral immunomodulators, and novel cytokines. Adoptive cellular strategies are evolving to TILS transduced with conditional gene expression cassettes, as well as non-T cell approaches involving dendritic cells and natural killer (NK) cells. Targeted therapy strategies have broadened to include upstream components of RAS, other MAP kinase pathways, and HDAC inhibitors, among others. All these new paradigms translate into increasingly complex decision-making for the treatment team, a burden that is more than offset by the tremendous benefit for melanoma patients. This is truly the beginning of a new era.

2026-01-08·ACS Medicinal Chemistry Letters

First-in-Class Potent, Dual HDAC6/Proteasome Inhibitors Lacking a Hydroxamic Acid Motif: Discovery of Novel Anti-Multiple Myeloma Agents

Article

作者: Aytenfisu, Asaminew H. ; MacKerell, Alexander D. ; Jones, Jace W. ; Chan, Alexandria M. ; Cottingham, Andrea L. ; Pearson, Ryan M. ; Fletcher, Steven ; Van Eker, Daniel ; Lowe, Brandon D.

Motivated by promising clinical trial data for the combination of the histone deacetylase 6 (HDAC6) inhibitor ricolinostat with the proteasome inhibitor bortezomib in relapsed/refractory multiple myeloma (MM) patients, we engineered dual HDAC6/proteasome inhibitors. FDA-approved HDAC inhibitors suffer from off-target effects, which have been attributed, in part, to their lack of HDAC isoform selectivity. Furthermore, they are potentially mutagenic, because of their indispensable hydroxamic acid zinc-binding groups (ZBGs). Deploying the HDAC6-selective phenyl-4-hydroxamic acid motif, and O-carbamoylated hydroxamates as hydroxamic acid surrogates, then grafting to the electrophilic boronic acid warhead of bortezomib/ixazomib, we discovered several dual HDAC6/proteasome inhibitors that were potent in cell-free assays, inhibiting the chymotrypsin-like (CL) proteasomal activity on par with that of bortezomib, and many compounds demonstrated selectivity for HDAC6 over HDAC1 as predicted. Moreover, several dual HDAC6/proteasome inhibitors were submicromolar inhibitors of MM cell growth. Of particular interest, AMC-3-030 with an O-(N-phenylcarbamoyl)-hydroxamate ZBG emerged as an exciting lead for further studies.

项与 HDAC inhibitors(Universitätsmedizin der Johannes Gutenberg-Universität Mainz) 相关的新闻（医药）

2025-10-23

·medivir.com

Medivir enters exclusive licensing agreement with Biossil, Inc. for remetinostat

Stockholm, Sweden — Medivir AB (Nasdaq Stockholm: MVIR), a pharmaceutical company focused on developing innovative treatments for cancer in areas of high unmet medical need, announces today that it has entered into an exclusive licensing agreement, through which Biossil, Inc. will receive global, exclusive development rights for remetinostat, a clinical-stage topical HDAC inhibitor. Biossil is a Toronto-based AI-native drug developer focused on developing novel therapies for heterogenous diseases with urgent unmet medical needs. Remetinostat has shown positive phase 2 data in basal cell carcinoma (BCC) as well as cutaneous T-cell lymphoma (CTCL). The terms of the agreement entitle Medivir, should remetinostat be successfully developed and approved, to receive payments up to a total of approximately USD 60 million, in addition to mid-single digit royalties on future net sales. - “Agreements, such as the one announced today with Biossil, continue to be a core component of Medivir’s corporate mission and business model,” said Jens Lindberg, Chief Executive Officer of Medivir. “Today’s announcement further exemplifies our focus and commitment to the development and commercialization of innovative treatments for cancer, and we look forward to Biossil’s progress with remetinostat in the clinic and beyond.” - “Remetinostat was identified with the same rigorous approach applied to all of Biossil candidates,” said Dr. Alexander Mosa, Co-Founder, Chief Scientific Officer and Chair of Biossil. “It meets our key criteria of promising clinical data, differentiated mechanism of action, and potential to address important unmet need. We are fortunate to have a supportive partner in Medivir, and we will resume development and advance remetinostat in accordance with its clinical potential.” For additional information, please contact; Magnus Christensen Chief Financial Officer Medivir AB M: +46 73 125 06 20 Email: Magnus.Christensen@medivir.com About remetinostat Remetinostat is a topical histone deacetylase (HDAC) inhibitor. Three clinical phase II studies, demonstrating remetinostat efficacy and safety, have been completed. The phase II study in mycosis-fungoides cutaneous T-cell lymphoma (MF-CTCL) showed reduced severity of CTCL skin lesions with an objective response rate (ORR) of 40% and a clinically significant reduction in the severity of pruritus (itching) in 80% of the patients. In addition, two investigator-initiated phase II studies have been conducted at Stanford University in the USA, demonstrating efficacy in cutaneous Squamous Cell Carcinoma (SCC), and showing 70% ORR and >50% complete histologic resolution in Basal Cell Carcinoma (BCC). About Medivir Medivir develops innovative drugs with a focus on cancer where the unmet medical needs are high. The drug candidates are directed toward indication areas where available therapies are limited or missing and there are great opportunities to offer significant improvements to patients. Medivir is focusing on the development of fostroxacitabine bralpamide (fostrox), a drug candidate designed to selectively treat cancer cells in the liver and to minimize side effects. Collaborations and partnerships are important parts of Medivir’s business model, and the drug development is conducted either by Medivir or in partnership. Medivir’s share (ticker: MVIR) is listed on Nasdaq Stockholm’s Small Cap list. www.medivir.com. About Biossil Biossil is an AI-native drug development company advancing a pipeline of late-stage, first-in-class candidates for heterogeneous and life-threatening diseases. With teams in Toronto and Boston, and partnerships with leading academic medical centers and research hospitals, Biossil integrates proprietary AI with deep clinical and translational expertise to rescue and reposition promising clinical-stage assets. This information is information that Medivir is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact persons set out above, at 2025-10-23 08:30 CEST. Attachments Press Release (PDF)

临床2期引进/卖出临床结果

2025-09-15

·cerenoscientific.com

Cereno Scientific Announces Conversion of All Remaining Convertibles Following Request by Fenja Capital II A/S and Arena Investors, LP

Cereno Scientific (Nasdaq First North: CRNO B) (“the Company”), an innovative biotech pioneering treatments to enhance and extend life for people with rare cardiovascular and pulmonary diseases, today announced that Fenja Capital II A/S and Arena Investors, LP (the “Financiers”) have called for the conversion of all remaining convertibles totaling SEK 25 million into new Class B shares in the Company, in accordance with the financing agreement (the “Financing Agreement”) entered into on 11 November 2024. The new Class B shares have today been registered with the Swedish Companies Registration Office (Bolagsverket). Conversion of the Convertibles As part of the Financing Agreement, convertibles were issued amounting to the nominal amount of SEK 75 million (the “Convertibles”). Previously, Convertibles amounting to SEK 50 million were converted into Class B shares in the Company in two separate conversions. The Financiers have now requested conversion of all remaining Convertibles to a total amount of SEK 25 million to new Class B to the pre-determined subscription price of 6.09 SEK per Class B share (the “Conversion”). Through the Conversion, the number of Class B shares in Cereno Scientific is increased by 4,105,090 Class B shares from 290,489,771 to 294,594,861 and the share capital is increased by SEK 410,509 from SEK 29,121,201.9 to SEK 29 531 710,90. The total number of votes in Cereno Scientific has increased by 4,105,090 votes, from 297,712,251 to 301,817,341 votes. This corresponds to a dilution effect of approximately 1.39 per cent of the currently outstanding shares in the Company and approximately 1.36 per cent of the currently outstanding votes in the Company. Following the Conversion, the Financiers do not hold any outstanding Convertibles. Further information can be found in the Company’s press releases: Cereno Scientific secures minimum 250 MSEK loan financing to reach set milestones into 2026 (November 11, 2024), Cereno Scientific secures 100 MSEK through additional loan financing and conversion to advance HDAC inhibitors CS1 and CS014 in Phase II (June 20, 2025) and Cereno Scientific announces conversion of convertibles following request by Fenja Capital II A/S and Arena Investors, LP (August 6, 2025). Completed registration The Class B shares have today been registered with the Swedish Companies Registration Office and the delivery of the Class B shares will be carried out without delay to the custody accounts designated by the Financiers. For further information, please contact: Tove Bergenholt, Head of IR & Communications Email: tove.bergenholt@cerenoscientific.com Phone: +46 73- 236 62 46 About Cereno Scientific AB Cereno Scientific is pioneering treatments to enhance and extend life. The company’s innovative pipeline offers disease-modifying drug candidates to empower people suffering from rare cardiovascular and pulmonary diseases to live life to the full. Lead candidate CS1 is an HDAC inhibitor that works through epigenetic modulation and represents a novel therapeutic approach by targeting the root mechanisms of the pulmonary arterial hypertension (PAH). CS1 is a well-tolerated oral therapy with a favorable safety profile that has shown encouraging efficacy signals of reverse vascular remodeling and improvement of right heart function as observed in a Phase IIa trial in patients with PAH. An Expanded Access Program enables patients that have completed the Phase IIa trial to gain access to CS1. CS014, in Phase I development, is a new chemical entity with disease-modifying potential. CS014 is a HDAC inhibitor with a multimodal mechanism of action as an epigenetic modulator having the potential to address the underlying pathophysiology of rare cardiovascular and pulmonary diseases with high unmet needs such as idiopathic pulmonary fibrosis (IPF). Cereno Scientific is also pursuing a preclinical program with CS585, an oral, highly potent and selective prostacyclin (IP) receptor agonist that has demonstrated the potential to significantly improve disease mechanisms relevant to cardiovascular diseases. While CS585 has not yet been assigned a specific indication for clinical development, preclinical data indicates that it could potentially be used in indications like Thrombosis prevention without increased risk of bleeding and Pulmonary Hypertension. The Company is headquartered in GoCo Health Innovation City, in Gothenburg, Sweden, and has a US subsidiary; Cereno Scientific Inc. based in Kendall Square, Boston, Massachusetts, US. Cereno Scientific is listed on the Nasdaq First North (CRNO B). The Company’s Certified Adviser is DNB Carnegie Investment Bank AB, certifiedadviser@carnegie.se. More information can be found on www.cerenoscientific.com. Read PDF Share

临床2期临床1期

100 项与 HDAC inhibitors(Universitätsmedizin der Johannes Gutenberg-Universität Mainz) 相关的药物交易

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