Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain

Alessandra Cipriano; Ciro Milite; Alessandra Feoli; Monica Viviano; Giacomo Pepe; Pietro Campiglia; Giuliana Sarno; Sarah Picaud; Satomi Imaide; Nikolai Makukhin; Panagis Filippakopoulos; Alessio Ciulli; Sabrina Castellano; Gianluca Sbardella

doi:10.1002/cmdc.202200343

Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain

Alessandra Cipriano, Ciro Milite, Alessandra Feoli, Monica Viviano, Giacomo Pepe, Pietro Campiglia, Giuliana Sarno, Sarah Picaud, Satomi Imaide, Nikolai Makukhin, Panagis Filippakopoulos, Alessio Ciulli, Sabrina Castellano (Lead / Corresponding author), Gianluca Sbardella

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

89 Downloads (Pure)

Abstract

The bromodomain and extra-terminal (BET) family of proteins includes BRD2, BRD3, BRD4, and the testis-specific protein, BRDT, each containing two N -terminal tandem bromodomain (BRD) modules. Potent and selective inhibitors targeting the two bromodomains are required to elucidate their biological role(s), with potential clinical applications. In this study, we designed and synthesized a series of benzimidazole-6-sulfonamides starting from the azobenzene compounds MS436 ( 7a ) and MS611 ( 7b ) that exhibited preference for the first (BD1) over the second (BD2) BRD of BET family members. The most-promising compound ( 9a ) showed good binding potency and improved metabolic stability and selectivity towards BD1 with respect to the parent compounds.

Original language	English
Article number	e202200343
Number of pages	14
Journal	ChemMedChem
Volume	17
Issue number	20
Early online date	30 Aug 2022
DOIs	https://doi.org/10.1002/cmdc.202200343
Publication status	Published - 19 Oct 2022

Keywords

Benzimidazole-6-sulfonamide
Bromodomain
Bioisosteres
Selectivity
Structure-activity relationships

Access to Document

10.1002/cmdc.202200343Licence: CC BY

Final Published VersionFinal published version, 6.94 MBLicence: CC BY

Cite this

Cipriano, A., Milite, C., Feoli, A., Viviano, M., Pepe, G., Campiglia, P., Sarno, G., Picaud, S., Imaide, S., Makukhin, N., Filippakopoulos, P., Ciulli, A., Castellano, S., & Sbardella, G. (2022). Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain. ChemMedChem, 17(20), Article e202200343. https://doi.org/10.1002/cmdc.202200343

@article{9262919b076d4f3ab6e8482a936747cd,

title = "Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain",

abstract = "The bromodomain and extra-terminal (BET) family of proteins includes BRD2, BRD3, BRD4, and the testis-specific protein, BRDT, each containing two N -terminal tandem bromodomain (BRD) modules. Potent and selective inhibitors targeting the two bromodomains are required to elucidate their biological role(s), with potential clinical applications. In this study, we designed and synthesized a series of benzimidazole-6-sulfonamides starting from the azobenzene compounds MS436 ( 7a ) and MS611 ( 7b ) that exhibited preference for the first (BD1) over the second (BD2) BRD of BET family members. The most-promising compound ( 9a ) showed good binding potency and improved metabolic stability and selectivity towards BD1 with respect to the parent compounds.",

keywords = "Benzimidazole-6-sulfonamide, Bromodomain, Bioisosteres, Selectivity, Structure-activity relationships",

author = "Alessandra Cipriano and Ciro Milite and Alessandra Feoli and Monica Viviano and Giacomo Pepe and Pietro Campiglia and Giuliana Sarno and Sarah Picaud and Satomi Imaide and Nikolai Makukhin and Panagis Filippakopoulos and Alessio Ciulli and Sabrina Castellano and Gianluca Sbardella",

note = "Funding Information: Biotechnology and Biological Sciences Research Council. Grant Number: BB/J001201/2; Wellcome Trust Biophysics and drug-discovery activities at Dundee. Grant Numbers: 100476/Z/12/Z, 094090/Z/10/Z",

year = "2022",

month = oct,

day = "19",

doi = "10.1002/cmdc.202200343",

language = "English",

volume = "17",

journal = "ChemMedChem",

issn = "1860-7179",

publisher = "Wiley",

number = "20",

}

Cipriano, A, Milite, C, Feoli, A, Viviano, M, Pepe, G, Campiglia, P, Sarno, G, Picaud, S, Imaide, S, Makukhin, N, Filippakopoulos, P, Ciulli, A, Castellano, S & Sbardella, G 2022, 'Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain', ChemMedChem, vol. 17, no. 20, e202200343. https://doi.org/10.1002/cmdc.202200343

TY - JOUR

T1 - Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain

AU - Cipriano, Alessandra

AU - Milite, Ciro

AU - Feoli, Alessandra

AU - Viviano, Monica

AU - Pepe, Giacomo

AU - Campiglia, Pietro

AU - Sarno, Giuliana

AU - Picaud, Sarah

AU - Imaide, Satomi

AU - Makukhin, Nikolai

AU - Filippakopoulos, Panagis

AU - Ciulli, Alessio

AU - Castellano, Sabrina

AU - Sbardella, Gianluca

N1 - Funding Information: Biotechnology and Biological Sciences Research Council. Grant Number: BB/J001201/2; Wellcome Trust Biophysics and drug-discovery activities at Dundee. Grant Numbers: 100476/Z/12/Z, 094090/Z/10/Z

PY - 2022/10/19

Y1 - 2022/10/19

N2 - The bromodomain and extra-terminal (BET) family of proteins includes BRD2, BRD3, BRD4, and the testis-specific protein, BRDT, each containing two N -terminal tandem bromodomain (BRD) modules. Potent and selective inhibitors targeting the two bromodomains are required to elucidate their biological role(s), with potential clinical applications. In this study, we designed and synthesized a series of benzimidazole-6-sulfonamides starting from the azobenzene compounds MS436 ( 7a ) and MS611 ( 7b ) that exhibited preference for the first (BD1) over the second (BD2) BRD of BET family members. The most-promising compound ( 9a ) showed good binding potency and improved metabolic stability and selectivity towards BD1 with respect to the parent compounds.

AB - The bromodomain and extra-terminal (BET) family of proteins includes BRD2, BRD3, BRD4, and the testis-specific protein, BRDT, each containing two N -terminal tandem bromodomain (BRD) modules. Potent and selective inhibitors targeting the two bromodomains are required to elucidate their biological role(s), with potential clinical applications. In this study, we designed and synthesized a series of benzimidazole-6-sulfonamides starting from the azobenzene compounds MS436 ( 7a ) and MS611 ( 7b ) that exhibited preference for the first (BD1) over the second (BD2) BRD of BET family members. The most-promising compound ( 9a ) showed good binding potency and improved metabolic stability and selectivity towards BD1 with respect to the parent compounds.

KW - Benzimidazole-6-sulfonamide

KW - Bromodomain

KW - Bioisosteres

KW - Selectivity

KW - Structure-activity relationships

UR - http://www.scopus.com/inward/record.url?scp=85138079605&partnerID=8YFLogxK

U2 - 10.1002/cmdc.202200343

DO - 10.1002/cmdc.202200343

M3 - Article

C2 - 36040095

SN - 1860-7179

VL - 17

JO - ChemMedChem

JF - ChemMedChem

IS - 20

M1 - e202200343

ER -

Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

A Systems Approach for the Fragment-based Development of Selective Chemical Probes of Bromodomain Function (joint with University of Oxford)

A Translational Engine for Biomedical Discoveries (Strategic Grant)

State-of-the-Art Facilities for Structural Biology at the University of Dundee

Cite this

Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Projects

A Systems Approach for the Fragment-based Development of Selective Chemical Probes of Bromodomain Function (joint with University of Oxford)

A Translational Engine for Biomedical Discoveries (Strategic Grant)

State-of-the-Art Facilities for Structural Biology at the University of Dundee

Cite this