Antileukemic activity and mechanism of action of the novel PI3K and histone deacetylase dual inhibitor CUDC-907 in acute myeloid leukemia

Li, Xinyu; Su, Yongwei; Madlambayan, Gerard J.; Edwards, Holly; Polin, Lisa; Kushner, Juiwanna; Dzinic, Sijana H.; White, Kathryn; Ma, Jun; Knight, Tristan; Wang, Guan; Wang, Yue; Yang, Jay; Taub, Jeffrey W.; Lin, Hai; Ge, Yubin

doi:10.3324/haematol.2018.201343

Cited by 60 publications

(80 citation statements)

References 43 publications

(52 reference statements)

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“…CUDC-907 induces apoptosis in AML cell lines and primary AML samples and shows in vivo efficacy in an AML cell-line-derived xenograft mouse model. CUDC-907-induced apoptosis was partially dependent on Mcl-1, Bim, and c-Myc, but downregulation of CHK1, Wee1, and RRM1 and induction of DNA damage contributed to CUDC-907-induced apoptosis of AML cells [141].…”

Section: Polypharmacology-based Approach Targeting Hdac Activity and mentioning

confidence: 91%

“…In AML patients PI3K/Akt pathway is constitutively active and preclinical studies demonstrate HDACIs enhance the effectiveness of PI3KIs. This observation prompted to explore the therapeutic potential of CUDC-907 in the treatment of AML [141]. CUDC-907 induces apoptosis in AML cell lines and primary AML samples and shows in vivo efficacy in an AML cell-line-derived xenograft mouse model.…”

Section: Polypharmacology-based Approach Targeting Hdac Activity and mentioning

confidence: 99%

“…This concept has resulted in the design and development of multitarget epigenetic hybrid drugs. Among the several epigenetic hybrid drugs produced, CUDC-907 is a promising single dual HDAC-PI3K inhibitor molecule with an ability to simultaneously inhibit HDACs and PI3K [15,16,[134][135][136][137][138][139][140][141][142][143][144]. CUDC-907 is an orally bioavailable small -molecule dual HDAC and PI3K inhibitor targeting class I and II HDACs and PI3Kα, β, and δ isoforms [135].…”

Section: Challenges and Concernsmentioning

confidence: 99%

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Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

Ranganna¹,

Selvam²,

Shivachar³

et al. 2020

IJMS

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Genetic mutations and aberrant epigenetic alterations are the triggers for carcinogenesis. The emergence of the drugs targeting epigenetic aberrations has provided a better outlook for cancer treatment. Histone deacetylases (HDACs) are epigenetic modifiers playing critical roles in numerous key biological functions. Inappropriate expression of HDACs and dysregulation of PI3K signaling pathway are common aberrations observed in human diseases, particularly in cancers. Histone deacetylase inhibitors (HDACIs) are a class of epigenetic small-molecular therapeutics exhibiting promising applications in the treatment of hematological and solid malignancies, and in non-neoplastic diseases. Although HDACIs as single agents exhibit synergy by inhibiting HDAC and the PI3K pathway, resistance to HDACIs is frequently encountered due to activation of compensatory survival pathway. Targeted simultaneous inhibition of both HDACs and PI3Ks with their respective inhibitors in combination displayed synergistic therapeutic efficacy and encouraged the development of a single HDAC-PI3K hybrid molecule via polypharmacology strategy. This review provides an overview of HDACs and the evolution of HDACs-based epigenetic therapeutic approaches targeting the PI3K pathway.

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Section: Polypharmacology-based Approach Targeting Hdac Activity and mentioning

confidence: 91%

Section: Polypharmacology-based Approach Targeting Hdac Activity and mentioning

confidence: 99%

Section: Challenges and Concernsmentioning

confidence: 99%

See 1 more Smart Citation

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

Ranganna¹,

Selvam²,

Shivachar³

et al. 2020

IJMS

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“…We therefore focused on CUDC-907 as the first choice for NNS. CUDC-907 is known to be a dual inhibitor of HDAC and PI3K-Akt and is an effective therapeutic candidate for AML, in which the PI3K-Akt pathway is constitutively activated [24]. However, there are no reports yet on its effect on the production of proinflammatory cytokines or chemokines.…”

Section: Cudc-907 Inhibits Mcp-1 and Ip-10 Production At A Lower Concmentioning

confidence: 99%

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Kase

Terashima

Ohta

et al. 2020

Preprint

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Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10.CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases. Significance statementIn this study, we identified a histone deacetylase inhibitor CUDC-907 as a potential effective compound for ameliorating overproduction of inflammatory chemokines in an autoinflammatory disease named Nakajo-Nishimura syndrome. We performed high-throughput screening using pluripotent stem cell-derived monocytic cell lines. Our data prove the validity of screening system as a versatile platform for seeking candidate compounds for the treatment of congenital immunological disorders associated with monocytic lineage cells.

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“…These observations fueled a lot of investigations on the anticancer properties of AF and its analogues, and on the underlying molecular mechanisms [ 2 , 3 , 4 , 5 ]. In recent years, new knowledge regarding the molecular mechanisms involved in leukemia cells growth has shifted the focus of antileukemic drug development to agents acting on specific molecular targets and pathways that regulate signal transduction, epigenetic alterations, cell death, and cell cycle progression [ 6 , 7 , 8 , 9 ]. In this regard, the ubiquitin-proteasome system seems to be a particularly attractive target [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

et al. 2020

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A group of triethylphosphine gold(I) and silver(I) complexes, structurally related to auranofin, were prepared and investigated as potential anticancer drug candidates. The antiproliferative properties of these metal compounds were assessed against two leukemia cell lines, i.e., CCRF-CEM and its multidrug-resistant counterpart, CEM/ADR5000. Interestingly, potent cytotoxic effects were disclosed for both series of compounds against leukemia cells, with IC50 values generally falling in the low-micromolar range, the gold derivatives being on the whole more effective than the silver analogues. Some initial structure-function relationships were drawn. Subsequently, the ability of the study compounds to inhibit the three main catalytic activities of the proteasome was investigated. Different patterns of enzyme inhibition emerged for the various metal complexes. Notably, gold compounds were able to inhibit effectively both the trypsin-like and chymotrypsin-like proteasome activities, being less effective toward the caspase-like catalytic activity. In most cases, a significant selectivity of the study compounds toward the proteasome proteolytic activities was detected when compared to other proteases. The implications of the obtained results are discussed.

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Antileukemic activity and mechanism of action of the novel PI3K and histone deacetylase dual inhibitor CUDC-907 in acute myeloid leukemia

Cited by 60 publications

References 43 publications

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

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