SETDB1 as a cancer target: challenges and perspectives in drug design

Hassanie, Haifa; Penteado, André Berndt; de Almeida, Larissa Costa; Calil, Raisa Ludmila; da Silva Emery, Flávio; Costa-Lotufo, Leticia Veras; Trossini, Gustavo Henrique Goulart

doi:10.1039/d3md00366c

RSC Med. Chem.

2024

DOI: 10.1039/d3md00366c

|View full text |Cite

SETDB1 as a cancer target: challenges and perspectives in drug design

Haifa Hassanie,

André Berndt Penteado,

Larissa Costa de Almeida

et al.

Abstract: Genome stability is governed by chromatin structural dynamics, which modify DNA accessibility under the influence of intra- and inter-nucleosomal contacts, histone post-translational modifications (PTMs) and variations, besides the activity of...

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...

Citation Types

Supporting

Mentioning

Contrasting

Year Published

2024

Publication Types

Select...

Preprint1

Relationship

Self Cite0

Independent1

Authors

Journals

Cited by 1 publication

References 176 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells

Uguen,

Shell,

Silva

et al. 2024

Preprint

View full text Add to dashboard Cite

A promising drug target, SETDB1, is a dual Kme reader and methyltransferase, which has been implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identified a low micromolar small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization led to the discovery of UNC10013, the first covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a kinact/KI of 1.0 x 106 M-1s-1 and demonstrated proteome-wide selectivity. In cells, negative allosteric modulation of SETDB1-mediated Akt methylation was observed after treatment with UNC10013. Therefore, UNC10013 is a potent, selective and cell-active covalent ligand for the 3TD of SETDB1, demonstrating negative allosteric modulator properties and making it a promising tool to study the biological role of SETDB1 in disease progression.

show abstract

Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells

Uguen,

Shell,

Silva

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

customersupport@researchsolutions.com

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Made with 💙 for researchers

Part of the Research Solutions Family.

SETDB1 as a cancer target: challenges and perspectives in drug design

Abstract: Genome stability is governed by chromatin structural dynamics, which modify DNA accessibility under the influence of intra- and inter-nucleosomal contacts, histone post-translational modifications (PTMs) and variations, besides the activity of...

Cited by 1 publication

References 176 publications

Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells

Potent and Selective SETDB1 Covalent Negative Allosteric Modulator Reduces Methyltransferase Activity in Cells

Contact Info

Product

Resources

About