Structure-activity relationship studies of SETD8 inhibitors

Anqi Ma; Wenyu Yu; Yan Xiong; Kyle V. Butler; Peter J. Brown; Jian Jin

doi:10.1039/c4md00317a

Structure-activity relationship studies of SETD8 inhibitors

Anqi Ma
, Wenyu Yu
, Yan Xiong
, Kyle V. Butler
, Peter J. Brown
, Jian Jin

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

30 Scopus citations

Abstract

SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and the proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1 and interesting SAR trends.

Original language	English
Pages (from-to)	1892-1898
Number of pages	7
Journal	MedChemComm
Volume	5
Issue number	12
DOIs	https://doi.org/10.1039/c4md00317a
State	Published - 1 Dec 2014

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title = "Structure-activity relationship studies of SETD8 inhibitors",

abstract = "SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and the proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1 and interesting SAR trends.",

author = "Anqi Ma and Wenyu Yu and Yan Xiong and Butler, \{Kyle V.\} and Brown, \{Peter J.\} and Jian Jin",

note = "Publisher Copyright: {\textcopyright} The Royal Society of Chemistry 2014.",

year = "2014",

month = dec,

day = "1",

doi = "10.1039/c4md00317a",

language = "English",

volume = "5",

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journal = "MedChemComm",

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TY - JOUR

T1 - Structure-activity relationship studies of SETD8 inhibitors

AU - Ma, Anqi

AU - Yu, Wenyu

AU - Xiong, Yan

AU - Butler, Kyle V.

AU - Brown, Peter J.

AU - Jin, Jian

PY - 2014/12/1

Y1 - 2014/12/1

N2 - SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and the proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1 and interesting SAR trends.

AB - SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and the proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1 and interesting SAR trends.

UR - https://www.scopus.com/pages/publications/84911883804

U2 - 10.1039/c4md00317a

DO - 10.1039/c4md00317a

M3 - Article

AN - SCOPUS:84911883804

SN - 2040-2503

VL - 5

SP - 1892

EP - 1898

JO - MedChemComm

JF - MedChemComm

IS - 12

ER -

Structure-activity relationship studies of SETD8 inhibitors

Abstract

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