PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia

Gawel, Justyna M.; Shouksmith, Andrew E.; Raouf, Yasir S.; Nawar, Nabanita; Toutah, Krimo; Bukhari, Shazreh; Manaswiyoungkul, Pimyupa; Olaoye, Olasunkanmi O.; Israelian, Johan; Radu, Tudor B.; Cabral, Aaron D.; Sina, Diana; Sedighi, Abootaleb; Araujo, Elvin D. de; Gunning, Patrick T.

doi:10.1016/j.ejmech.2020.112411

Cited by 33 publications

(22 citation statements)

References 38 publications

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“…HDAC6 deacetylates cytoplasmic proteins such as tubulin and HSP90, and has important functions in tumorigenesis, such as modulation of protein homeostasis through regulation of HSP90 and proteasomal degradation [ 245 , 246 , 247 ], p53 apoptotic activity [ 248 ], and tyrosine kinase signaling [ 249 ]. As a result, several groups have contributed to the development of HDAC6-selective inhibitors [ 250 , 251 , 252 ]. Ricolinostat, an HDAC6-selective inhibitor, was effective in models of multiple myeloma and lymphoma in vitro and in vivo [ 253 , 254 ].…”

Section: Dissecting the Variables Of Hdac Inhibitionmentioning

confidence: 99%

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

Karagiannis

Ράμπιας

2021

Cancers

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Intra-tumoral heterogeneity presents a major obstacle to cancer therapeutics, including conventional chemotherapy, immunotherapy, and targeted therapies. Stochastic events such as mutations, chromosomal aberrations, and epigenetic dysregulation, as well as micro-environmental selection pressures related to nutrient and oxygen availability, immune infiltration, and immunoediting processes can drive immense phenotypic variability in tumor cells. Here, we discuss how histone deacetylase inhibitors, a prominent class of epigenetic drugs, can be leveraged to counter tumor heterogeneity. We examine their effects on cellular processes that contribute to heterogeneity and provide insights on their mechanisms of action that could assist in the development of future therapeutic approaches.

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Section: Dissecting the Variables Of Hdac Inhibitionmentioning

confidence: 99%

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

Karagiannis

Ράμπιας

2021

Cancers

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“…In addition to acting as transcription repressors, class II HDACs are associated with autophagic progression and cytoskeleton microtubules ( 44 ). For example, HDAC6 can act as a α-tubulin deacetylase and participate in multiple cytoplasmic pathways related to microtubules ( 45 , 46 ), revealing that it may be an important therapeutic for treating Alzheimer’s disease and cancer ( 47 ). HDAC4 and HDAC9 contain different common genomic binding sites.…”

Section: Hdac Classificationsmentioning

confidence: 99%

Characterization of Histone Deacetylase Mechanisms in Cancer Development

Hai

Shu

et al. 2021

Front. Oncol.

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Over decades of studies, accumulating evidence has suggested that epigenetic dysregulation is a hallmark of tumours. Post-translational modifications of histones are involved in tumour pathogenesis and development mainly by influencing a broad range of physiological processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are pivotal epigenetic modulators that regulate dynamic processes in the acetylation of histones at lysine residues, thereby influencing transcription of oncogenes and tumour suppressor genes. Moreover, HDACs mediate the deacetylation process of many nonhistone proteins and thus orchestrate a host of pathological processes, such as tumour pathogenesis. In this review, we elucidate the functions of HDACs in cancer.

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“…Tubacin, the first selective HDAC6 inhibitor, was developed by Schreiber et al by diversity-oriented synthesis [110]. Now HDAC6 inhibitors have reached the clinic, where they are tested against MM, biliary tract cancers and AML [111].…”

Section: Accepted Articlementioning

confidence: 99%

Therapeutic targeting of chromatin: status and opportunities

Siklos

Kubicek

2021

The FEBS Journal

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The molecular characterization of mechanisms underlying transcriptional control and epigenetic inheritance since the 1990s has paved the way for the development of targeted therapies that modulate these pathways. In the past two decades, cancer genome sequencing approaches have uncovered a plethora of mutations in chromatin modifying enzymes across tumor types, and systematic genetic screens have identified many of these proteins as specific vulnerabilities in certain cancers. Now is the time when many of these basic and translational efforts start to bear fruit and more and more chromatin‐targeting drugs are entering the clinic. At the same time, novel pharmacological approaches harbor the potential to modulate chromatin in unprecedented fashion, thus generating entirely novel opportunities. Here, we review the current status of chromatin targets in oncology and describe a vision for the epigenome‐modulating drugs of the future.

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PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia

Cited by 33 publications

References 38 publications

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

Characterization of Histone Deacetylase Mechanisms in Cancer Development

Therapeutic targeting of chromatin: status and opportunities

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