Histone deacetylases as an epigenetic pillar for the development of hybrid inhibitors in cancer

Stazi, Giulia; Fioravanti, Rossella; Mai, Antonello; Mattevi, Andrea

doi:10.1016/j.cbpa.2019.03.002

Cited by 24 publications

(26 citation statements)

References 64 publications

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“…In this context, novel approaches and combinatorial schemes that involve LSD1 inhibitors are underway. For example, numerous novel inhibitors (called chimeric or hybrid) have been designed, so that single molecules can be directed against multiple targets [133]. This new class of epigenetic inhibitors includes the LSD1/HDAC hybrid inhibitors that target simultaneously LSD1 and HDAC1 or HDAC1/2 [134][135][136].…”

Section: Lsd1 As a Therapeutic Target In Cancer Treatmentmentioning

confidence: 99%

“…This new class of epigenetic inhibitors includes the LSD1/HDAC hybrid inhibitors that target simultaneously LSD1 and HDAC1 or HDAC1/2 [134][135][136]. Such drugs guarantee the combined effect at multiple targets in the very same cell, apart from the more favorable pharmacokinetic or pharmacodynamic parameters or their more predictable and less complex metabolism [133]. Other novel therapeutic approaches involve combinatorial treatment regimens that utilize epigenetic agents to prime the activity of the second agent [121].…”

Section: Lsd1 As a Therapeutic Target In Cancer Treatmentmentioning

confidence: 99%

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LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

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A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing cancer stemness characteristics, such as self-renewal and chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role in the normal hematopoietic and neuronal stem cells. Overexpression of LSD1 has been documented in a variety of cancers, where the enzyme is, usually, associated with the more aggressive types of the disease. Interestingly, recent studies have implicated LSD1 in the regulation of the pool of CSCs in different leukemias and solid tumors. However, the precise mechanisms that LSD1 uses to mediate its effects on cancer stemness are largely unknown. Herein, we review the literature on LSD1’s role in normal and cancer stem cells, highlighting the analogies of its mode of action in the two biological settings. Given its potential as a pharmacological target, we, also, discuss current advances in the design of novel therapeutic regimes in cancer that incorporate LSD1 inhibitors, as well as their future perspectives.

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Section: Lsd1 As a Therapeutic Target In Cancer Treatmentmentioning

confidence: 99%

Section: Lsd1 As a Therapeutic Target In Cancer Treatmentmentioning

confidence: 99%

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

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“…Originally, HDACIs were known for their varied cellular effects on cancer cells, such as inhibiting cell proliferation and stimulating differentiation or apoptosis, advocating their usefulness in anticancer drug discovery, and development [80,81]. Now, it is recognized HDACIs induce an array of cellular effects [69,82,83]. They stimulate cell cycle arrest by upregulating p21Cip1 and downregulating cyclins [69,84,85].…”

Section: Histone Deacetylase Inhibitors (Hdacis)mentioning

confidence: 99%

“…3) Promote anti-angiogenic effect by altering Hif-1α function and downregulation of VEGF [89]. 4) Alter expression of nonhistone proteins including transcription factors and regulators, inflammation/immune response mediators, chaperones, DNA repair enzymes, and structural proteins [69,82,83,90]. These features of HDACIs are exploited as promising anticancer epi-drugs and several HDACIs have entered clinical trials in both hematologic and solid tumors [70,[72][73][74][75][81][82][83]90].…”

Section: Histone Deacetylase Inhibitors (Hdacis)mentioning

confidence: 99%

“…4) Alter expression of nonhistone proteins including transcription factors and regulators, inflammation/immune response mediators, chaperones, DNA repair enzymes, and structural proteins [69,82,83,90]. These features of HDACIs are exploited as promising anticancer epi-drugs and several HDACIs have entered clinical trials in both hematologic and solid tumors [70,[72][73][74][75][81][82][83]90]. As such, HDACIs are investigated mainly as anticancer epi-drugs, even though HDAC enzymes also play a crucial role in other diseases such as cardiovascular disease [91], neurological disorders [92], immunological processes and viral infections [93], and other disorders [94].…”

Section: Histone Deacetylase Inhibitors (Hdacis)mentioning

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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Novel Pyridine‐Based Hydroxamates and 2′‐Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity

et al. 2020

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Starting from the N‐hydroxy‐3‐(4‐(2‐phenylbutanoyl)amino)phenyl)acrylamide (5 b) previously described by us as a HDAC inhibitor, we prepared four aza‐analogues, 6–8, 9 b, as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N‐hydroxy‐5‐(2‐(2‐phenylbutanoyl)amino)pyridyl)acrylamide (9 b) as the most potent inhibitor. Thus, we further developed both pyridylacrylic‐ and nicotinic‐based hydroxamates (9 a, 9 c–f, and 11 a–f) and 2′‐aminoanilides (10 a–f and 12 a–f), related to 9 b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub‐nanomolar potency (IC50: 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2′‐aminoanilides were class I‐selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC50HDAC3=0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9 e, 11 c, and 11 d blocked over 80 % of cells in G2/M phase, whereas the anilides did not alter cell‐cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30 % apoptosis, and the anilide 12 c displayed about 40 % cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b, 11 c, 10 b, 10 e, and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC50 values at single‐digit to sub‐micromolar level.

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Histone deacetylases as an epigenetic pillar for the development of hybrid inhibitors in cancer

Cited by 24 publications

References 64 publications

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

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

Novel Pyridine‐Based Hydroxamates and 2′‐Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity

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