Thiol-based potent and selective HDAC6 inhibitors promote tubulin acetylation and T-regulatory cell suppressive function

Mariana C.F. Segretti; Gian Paolo Vallerini; Camille Brochier; Brett Langley; Liqing Wang; Wayne W. Hancock; Alan P. Kozikowski

doi:10.1021/acsmedchemlett.5b00303

Thiol-based potent and selective HDAC6 inhibitors promote tubulin acetylation and T-regulatory cell suppressive function

Mariana C.F. Segretti, Gian Paolo Vallerini, Camille Brochier, Brett Langley, Liqing Wang, Wayne W. Hancock, Alan P. Kozikowski

School of Medicine

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

26 Scopus citations

Abstract

Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. 2b also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 μM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation in vitro.

Original language	English (US)
Pages (from-to)	1156-1161
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	6
Issue number	11
DOIs	https://doi.org/10.1021/acsmedchemlett.5b00303
State	Published - Nov 12 2015

Keywords

1,2,3,4-tetrahydroquinoline
8-aminoquinoline
HDAC6-selective inhibitors
Treg
mercaptoacetamides

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1021/acsmedchemlett.5b00303

Cite this

@article{b1e143b8c1da41a5bf7e4bf7f8f628f4,

title = "Thiol-based potent and selective HDAC6 inhibitors promote tubulin acetylation and T-regulatory cell suppressive function",

abstract = "Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. 2b also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 μM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation in vitro.",

keywords = "1,2,3,4-tetrahydroquinoline, 8-aminoquinoline, HDAC6-selective inhibitors, Treg, mercaptoacetamides",

author = "Segretti, {Mariana C.F.} and Vallerini, {Gian Paolo} and Camille Brochier and Brett Langley and Liqing Wang and Hancock, {Wayne W.} and Kozikowski, {Alan P.}",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2015",

month = nov,

day = "12",

doi = "10.1021/acsmedchemlett.5b00303",

language = "English (US)",

volume = "6",

pages = "1156--1161",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "11",

}

TY - JOUR

T1 - Thiol-based potent and selective HDAC6 inhibitors promote tubulin acetylation and T-regulatory cell suppressive function

AU - Segretti, Mariana C.F.

AU - Vallerini, Gian Paolo

AU - Brochier, Camille

AU - Langley, Brett

AU - Wang, Liqing

AU - Hancock, Wayne W.

AU - Kozikowski, Alan P.

PY - 2015/11/12

Y1 - 2015/11/12

N2 - Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. 2b also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 μM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation in vitro.

AB - Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1. 2b also showed excellent efficacy at increasing tubulin acetylation in rat primary cortical cultures, inducing a 10-fold increase in acetylated tubulin at 1 μM. To assess possible therapeutic effects, compounds were assayed for their ability to increase T-regulatory (Treg) suppressive function. Some but not all of the compounds increased Treg function, and thereby decreased conventional T cell activation and proliferation in vitro.

KW - 1,2,3,4-tetrahydroquinoline

KW - 8-aminoquinoline

KW - HDAC6-selective inhibitors

KW - Treg

KW - mercaptoacetamides

UR - http://www.scopus.com/inward/record.url?scp=84947422205&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84947422205&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.5b00303

DO - 10.1021/acsmedchemlett.5b00303

M3 - Article

C2 - 26617971

AN - SCOPUS:84947422205

SN - 1948-5875

VL - 6

SP - 1156

EP - 1161

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 11

ER -

Thiol-based potent and selective HDAC6 inhibitors promote tubulin acetylation and T-regulatory cell suppressive function

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this