Potent non-hydroxamate inhibitors of histone deacetylase-8: Role and scope of an isoindolin-2-yl linker with an α-amino amide as the zinc-binding unit

doi:10.1016/j.bmcl.2019.126926

Bioorganic & Medicinal Chemistry Letters

Volume 30, Issue 5, 1 March 2020, 126926

https://doi.org/10.1016/j.bmcl.2019.126926 Get rights and content

Abstract

A series of potent inhibitors of histone deacetylase-8 (HDAC8) is described that contains an α-amino amide zinc-binding unit and a substituted isoindolinyl capping group. The presence of a 2,4-dichlorophenyl unit located in the acetate-release cavity was shown to confer a gain of approx. 4.3 kJ mol⁻¹ in binding energy compared to a phenyl group, and the isoindoline linker has approx. 5.8 kJ mol⁻¹ greater binding energy than the corresponding tetrahydroisoquinoline ring system. In a series of 5-substituted isoindolin-2-yl inhibitors, a 5-acetylamino derivative was found to be more potent than the 5-unsubstituted lead HDAC8 inhibitor (increase in binding energy of 2.0 kJ mol⁻¹, ascribed to additional binding interactions within the N_ε-acetyl-l-lysine binding tunnel in HDAC8, including hydrogen bonding to Asp101. Tolerance of a 5-substituent (capping group) on the isoindoline ring has been demonstrated, and which in some cases confers improved enzyme inhibition, the HDAC8 substrate-binding region providing a platform for additional interactions.

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Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Financial support from the BBSRC for a studentship (to S. O. R. G.) is gratefully acknowledged. D. F. H. acknowledges the BBSRC for financial support (BB/H022570/1). We are grateful to Dr Christopher Matthews for providing the MAL substrate and to Drs Nicolas D. Werbeck and Micha B. A. Kunze for assistance with in vitro assays and dockings, and for helpful discussions.

References (36)

C.A. Hassig et al.
Curr Opin Chem Biol
(1997)
J.M. Maris et al.
Lancet
(2007)
K. KrennHrubec et al.
Bioorg Med Chem Lett
(2007)
W. Tang et al.
Bioorg Med Chem Lett
(2011)
L. Whitehead et al.
Bioorg Med Chem
(2011)
V.M. Richon et al.
Cancer Lett
(2009)
W.K. Kelly et al.
J Clin Oncol
(2005)
C.A. Chang et al.
Proc Natl Acad Sci
(2007)
S. Kalyaanamoorthy et al.
J Comput Chem
(2013)
T. Kouzarides
EMBO J
(2000)
T. Jenuwein et al.
Science
(2001)

J. Taunton et al.

Science

(1996)

B.D. Strahl et al.

Nature

(2000)

C.M. Marson

Anti-Cancer Agents Med Chem

(2009)

S. Minucci et al.

Nat Rev Cancer

(2006)

U. Mahlknecht et al.

Mol Med

(2000)

S.A. Gayther et al.

Nat Genet

(2000)

I. Oehme et al.

Clin Cancer Res

(2009)

G.M. Brodeur

Nat Rev Cancer

(2003)

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Potent non-hydroxamate inhibitors of histone deacetylase-8: Role and scope of an isoindolin-2-yl linker with an α-amino amide as the zinc-binding unit

Abstract

Graphical abstract

Section snippets

Declaration of Competing Interest

Acknowledgments

Curr Opin Chem Biol

Lancet

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Bioorg Med Chem

Cancer Lett

J Clin Oncol

Proc Natl Acad Sci

J Comput Chem

EMBO J

Science

Science

Nature

Anti-Cancer Agents Med Chem

Nat Rev Cancer

Mol Med

Nat Genet

Clin Cancer Res

Nat Rev Cancer