First-in-human study of 4SC-202, a novel oral HDAC inhibitor in advanced hematologic malignancies (TOPAS study).

Tresckow, Bastian von; Gundermann, Stefan; Eichenauer, Dennis A.; Aulitzky, Walter; Göbeler, Mariele; Sayehli, Cyrus; Bacchus, L.; Hametner, Bernhard; Mestice, Anna; Hentsch, Bernd; Kohlhof, Hella; Krauss, Rolf; Krauss, Babett; Baumgartner, Roland; Vitt, Daniel; Engert, Andreas

doi:10.1200/jco.2014.32.15_suppl.8559

Cited by 10 publications

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“…64 This drug has been studied in a phase I trial (ClinicalTrials.gov identifier, NCT01344707; TOPAS [oral histone deacetylase inhibitor 4SC-202 in patients with advanced hematologic malignancies]) of 24 patients with advanced hematologic malignancies, including MM. The drug was welltolerated, and 20 of the patients (83%) were reported to have derived clinical benefit, 65 although details concerning the study have not yet been reported. BG45 is an HDAC3-selective inhibitor that has shown promise in MM in preclinical studies.…”

Section: Class-and/or Isotype-selective Hdac Inhibitorsmentioning

confidence: 99%

The Multiple Myeloma Drug Pipeline—2018: A Review of Small Molecules and Their Therapeutic Targets

Abramson

2018

Clinical Lymphoma Myeloma and Leukemia

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Treatment of multiple myeloma (MM), a neoplasm of plasma cells, formerly dependent on alkylating drugs, corticosteroids, and autologous stem cell transplantation, has changed dramatically in the past 20 years because 3 new classes of small molecule drugs (arbitrarily defined as having a molecular weight of < 900 kDa)-immunomodulators, proteasome inhibitors, and histone deacetylase blockers-have been introduced for the disease. Therapeutic options for MM expanded further in 2015 when 2 new monoclonal antibodies (daratumumab and elotuzumab) were approved by the Food and Drug Administration for MM. Although MM remains incurable, the cumulative effect of these advances has resulted in a near-doubling of the 5-year survival rate since the late 1980s. Despite these advances, therapy for MM continues to pose substantial challenges because resistance to therapy frequently develops, and relapse and recurrence are all too common. The present review focused on the pipeline for new small molecules in various stages of development and their associated cellular targets. In addition to newer versions of alkylators, immunomodulators, proteasome inhibitors, and histone deacetylase inhibitors, the present review considered the prospects for adding new classes of small molecules to the MM armamentarium, which offer the potential for oral efficacy, relative simplicity of preparation, and prospects for improvement in the cost-to-benefit ratio. Included are agents that affect myeloma epigenetics and the ubiquitination-proteasome system and the unfolded protein response, apoptotic mechanisms, chromosomal abnormalities, nuclear protein transport, and various kinases involved in cellular signaling pathways.

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Section: Class-and/or Isotype-selective Hdac Inhibitorsmentioning

confidence: 99%

The Multiple Myeloma Drug Pipeline—2018: A Review of Small Molecules and Their Therapeutic Targets

Abramson

2018

Clinical Lymphoma Myeloma and Leukemia

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“…In addition, LSD1 inhibitors GSK354 and GSK690 have recently been reported to inhibit cell growth in vitro (101). Interestingly, the small molecule HDAC inhibitor 4SC-202 has a dual function to inhibit LSD1 with similar potency and is in clinical trials for patients with advanced hematologic malignancies (102).…”

Section: Targeting Histone Demethylationmentioning

confidence: 99%

Targeting Epigenetics in Cancer

Bennett

Licht

2018

Annu. Rev. Pharmacol. Toxicol.

210

142

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Alterations of genes regulating epigenetic processes are frequently found as cancer drivers and may cause widespread alterations of DNA methylation, histone modification patterns, or chromatin structure that disrupt normal patterns of gene expression. Because of the inherent reversibility of epigenetic changes, inhibitors targeting these processes are promising anticancer strategies. Small molecules targeting epigenetic regulators have been developed recently, and clinical trials of these agents are under way for hematologic malignancies and solid tumors. In this review, we describe how the writers, readers, and erasers of epigenetic marks are dysregulated in cancer and summarize the development of therapies targeting these mechanisms.

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“…4SC-202 provokes the inhibition of stemness-related properties of cancer cells and affects their viability [ 157 ]. It has, in March 2015, ended a phase I trial in patients with advanced hematological malignancies, and it showed to be well tolerated and to possess anti-cancer activity (ClinicalTrials.gov identifier: NCT01344707) [ 158 ]. Very interesting is also the reported synergistic lethal effect against cultured and primary AML blasts showed by the combination of SP2509, a very potent LSD1 inhibitor with panobinostat, a pan-HDAC inhibitor.…”

Section: Lsd1/kdm1amentioning

confidence: 99%

Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy

2016

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The term epigenetics is defined as heritable changes in gene expression that are not due to alterations of the DNA sequence. In the last years, it has become more and more evident that dysregulated epigenetic regulatory processes have a central role in cancer onset and progression. In contrast to DNA mutations, epigenetic modifications are reversible and, hence, suitable for pharmacological interventions. Reversible histone methylation is an important process within epigenetic regulation, and the investigation of its role in cancer has led to the identification of lysine methyltransferases and demethylases as promising targets for new anticancer drugs. In this review, we describe those enzymes and their inhibitors that have already reached the first stages of clinical trials in cancer therapy, namely the histone methyltransferases DOT1L and EZH2 as well as the demethylase LSD1.

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First-in-human study of 4SC-202, a novel oral HDAC inhibitor in advanced hematologic malignancies (TOPAS study).

Cited by 10 publications

References 0 publications

The Multiple Myeloma Drug Pipeline—2018: A Review of Small Molecules and Their Therapeutic Targets

The Multiple Myeloma Drug Pipeline—2018: A Review of Small Molecules and Their Therapeutic Targets

Targeting Epigenetics in Cancer

Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy

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