Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

Kalin, Jay H.; Wu, Muzhou; Gómez, Andrea V.; Song, Yun; Das, Jayanta; Hayward, Dawn; Adejola, Nkosi; Wu, Mingxuan; Panova, Izabela P.; Chung, Hye Jin; Kim, Edward; Roberts, Holly J.; Roberts, Justin M.; Prusevich, Polina; Jeliazkov, Jeliazko R.; Burman, Shourya S. Roy; Fairall, Louise; Milano, Charles P.; Eroglu, Abdulkerim; Proby, Charlotte M.; Dinkova‐Kostova, Albena T.; Hancock, Wayne W.; Gray, Jeffrey J.; Bradner, James E.; Valente, Sérgio; Mai, Antonello; Anders, Nicole M.; Rudek, Michelle A.; Hu, Yong; Ryu, Byungwoo; Schwabe, John W. R.; Mattevi, Andrea; Alani, Rhoda M.; Cole, Philip A.

doi:10.1038/s41467-017-02242-4

Cited by 193 publications

(183 citation statements)

References 46 publications

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“…Here, we characterize and clinically validate domatinostat (4SC‐202) as an orally available small molecule, selective class I HDACi that efficiently and selectively blocks HDACs 1, 2, and 3. Although some activity against LSD1 was observed using purified enzyme, the dual inhibitory activity against HDAC and LSD1 of domatinostat remains ambiguous and may require additional experiments . In cell‐based assays, the compound showed potent inhibition of viability in several human hematological tumor cell lines.…”

Section: Discussionmentioning

confidence: 91%

Phase I study of domatinostat (4SC‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

Tresckow

Sayehli

Aulitzky

et al. 2019

European J of Haematology

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Objectives Domatinostat (4SC‐202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. Methods Domatinostat was administered orally once (QD) or twice daily (BID) on days 1‐14 with 7 days off or continuously days 1‐21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty‐four patients were treated with domatinostat. Results No formal maximum tolerated dose (MTD) was determined. One dose‐limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment‐related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. Conclusion Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy.

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Section: Discussionmentioning

confidence: 91%

Phase I study of domatinostat (4SC‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

Tresckow

Sayehli

Aulitzky

et al. 2019

European J of Haematology

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“…However, CoRest1 functions in diverse processes due to its many binding partners. Recent work has shown requirements for CoRest1 in hematopoiesis, promoting viral latency following infection and in a variety of cancers . Zebrafish rcor1 mutants have decreased fitness, but their outward appearances appear to be healthy suggesting that the fish rcor1 mutants compensate for lack of the protein.…”

Section: Discussionmentioning

confidence: 99%

CoRest1 regulates neurogenesis in a stage‐dependent manner

Monestime

Taibi

Gates

et al. 2019

Developmental Dynamics

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Background Developmental processes, including neuronal differentiation, require precise regulation of transcription. The RE‐1 silencing transcription factor (Rest), is often called a “master neuronal regulator” due to its large number of neural‐specific targets. Rest recruits CoRest (Rcor) and Sin3 corepressor complexes to gene regulatory sequences. CoRest not only associates with Rest, but with other transcription regulators. In this study, we generated zebrafish rcor1 mutants using transcription activator‐like effector nucleases (TALENS), to study its requisite role in repression of Rest target genes as well as Rest‐independent Rcor1 developmental functions. Results While rcor1 mutants have a slight decrease in fitness, most survived and produced viable offspring. We examined expression levels of RE1‐containing genes in maternal zygotic rcor1 (MZrcor1) mutants and found that Rcor1 is generally not required for the repression of Rest target genes at early stages. However, MZrcor1 mutants undergo more rapid neurogenesis compared to controls. We found that at gastrula stages, Rcor1 acts as a repressor of her gene family, but at later stages, her6 decreased in the MZrcor1 mutant. Conclusions Based on these findings, the central role of CoRest1 in neurogenesis is likely due to a Rest‐independent role rather than as a Rest corepressor.

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“…The most potent compound, 114 (Figure ), bound the CoREST ternary complex showing both LSD1 and HDAC1 inhibition at submicromolar level, and exhibited higher antiproliferative activity than entinostat 9 against cutaneous squamous carcinoma and several melanoma cell lines, being less toxic than 9 towards keratinocytes and melanocytes. Importantly, 114 slowed down tumor growth in a melanoma mouse xenograft model …”

Section: The Mtdl Approachmentioning

confidence: 99%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

Cited by 193 publications

References 46 publications

Phase I study of domatinostat (4SC‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

Phase I study of domatinostat (4SC‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

CoRest1 regulates neurogenesis in a stage‐dependent manner

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

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