Identification of Structural Features of 2‐Alkylidene‐1,3‐Dicarbonyl Derivatives that Induce Inhibition and/or Activation of Histone Acetyltransferases KAT3B/p300 and KAT2B/PCAF

Castellano, Sabrina; Milite, Ciro; Feoli, Alessandra; Viviano, Monica; Mai, Antonello; Novellino, Ettore; Tosco, Alessandra; Sbardella, Gianluca

doi:10.1002/cmdc.201402371

Cited by 22 publications

(13 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7b and d ). The direct binding of SR141716 to the HAT catalytic domain (aa 1284–1673) of human recombinant p300/KAT3B was corroborated by the results of a surface plasmon resonance (SPR) assay, performed according to a well-established protocol 38 , 39 . In fact, Fig.…”

Section: Resultsmentioning

confidence: 85%

Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer

Proto

Fiore

Piscopo

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

In a high percentage (≥85%) of both sporadic and familial adenomatous polyposis forms of colorectal cancer (CRC), the inactivation of the APC tumor suppressor gene initiates tumor formation and modulates the Wnt/β-Catenin transduction pathways involved in the control of cell proliferation, adhesion and metastasis. Increasing evidence showed that the endocannabinoids control tumor growth and progression, both in vitro and in vivo. We evaluated the effect of Rimonabant, a Cannabinoid Receptor 1 (CB1) inverse agonist, on the Wnt/β-Catenin pathway in HCT116 and SW48 cell lines carrying the genetic profile of metastatic CRC poorly responsive to chemotherapies. In these models, Rimonabant inhibited the Wnt/β-Catenin canonical pathway and increased β-Catenin phosphorylation; in HCT116 cells, but not in SW48, the compound also triggered the Wnt/β-Catenin non canonical pathway activation through induction of Wnt5A and activation of CaMKII. The Rimonabant-induced downregulation of Wnt/β-Catenin target genes was partially ascribable to a direct inhibition of p300/KAT3B histone acetyltransferase, a coactivator of β-Catenin dependent gene regulation. Finally, in HCT116 xenografts, Rimonabant significantly reduced tumor growth and destabilized the nuclear localization of β-Catenin. Obtained data heavily supported the rationale for the use of cannabinoids in combined therapies for metastatic CRC harbouring activating mutations of β-Catenin.

show abstract

Section: Resultsmentioning

confidence: 85%

Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer

Proto

Fiore

Piscopo

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several epigenetic inhibitors have been developed and shown to induce differentiation, growth arrest, or apoptosis in tumor cells [7][8][9][10][39][40][41]. Among them, we previously characterized the thiazole derivative CPTH6, as a novel HAT inhibitor that activates the apoptotic program and modulates the autophagic flux in human tumor cell lines [11,12].…”

Section: Discussionmentioning

confidence: 99%

“…Histone acetyltransferase inhibitors (HATi) belong to the family of epigenetic drugs and represent a heterogeneous group of compounds able to alter histone and nonhistone protein functions [6]. Several molecules with HAT inhibitory activity have been identified and some of them showed to induce cell death preferentially in cancer cells when compared to normal ones [6][7][8][9][10]. Among them, the thiazole derivative 3-methyl-cyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl)]hydrazone (CPTH6), has been characterized by our group as a novel Gcn5 and pCAF HAT inhibitor, able to activate the apoptotic program and to modulate the autophagic flux in a panel of tumor cell lines [11,12].…”

Section: Introductionmentioning

confidence: 99%

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Martile¹,

Desideri²,

Luca³

et al. 2016

European Journal of Cancer

View full text Add to dashboard Cite

Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.

show abstract

“…Important to highlight in this family of compounds are the unique properties of pentadecylidenemalonate 1b (SPV106), that leads to PCAF (KAT2B) acetylation activity increase, together with its inhibitory properties against CBP (KAT3A) and p300 (KAT3B) 168,169 . This inspired the synthesis of SVP106 analogs that feature different levels of activity modulation for KAT2B and KAT3B simultaneously 170 . SPV106 has been successfully used in neurological 171 and cardiological 172,173 studies where the acetylation activity of KAT2B was investigated.…”

Section: Targeting Protein Acetylation Beyond Bromodomain Inhibition mentioning

confidence: 99%

Bromodomain inhibitors and cancer therapy: From structures to applications

2016

View full text Add to dashboard Cite

Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are “writers,” “erasers,” or “readers” of histone modification marks are common. Bromodomains are “readers” that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. In recent years, there has been increasing interest in developing small molecules that can target specific bromodomains. First, this has helped clarify biological functions of bromodomain-containing proteins. Secondly, it opens a new front for combatting cancer. In this review we will describe the structures and mechanisms associated with Bromodomain and Extra-Terminal motif (BET) inhibitors and non-BET inhibitors, their current status of development, and their promising role as anti-cancer agents.

show abstract

Identification of Structural Features of 2‐Alkylidene‐1,3‐Dicarbonyl Derivatives that Induce Inhibition and/or Activation of Histone Acetyltransferases KAT3B/p300 and KAT2B/PCAF

Cited by 22 publications

References 112 publications

Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer

Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Bromodomain inhibitors and cancer therapy: From structures to applications

Contact Info

Product

Resources

About