Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

Chuhui Huang; Si Si Liew; Grace R. Lin; Anders Poulsen; Melgious J.Y. Ang; Brian C.S. Chia; Sin Yin Chew; Zekui P. Kwek; John L.K. Wee; Esther H. Ong; Priya Retna; Nithya Baburajendran; Rong Li; Weixuan Yu; Xiaoying Koh-Stenta; Anna Ngo; Sravanthy Manesh; Justina Fulwood; Zhiyuan Ke; Hwa Hwa Chung; Sugunavathi Sepramaniam; Xin Hui Chew; Nurul Dinie; May Ann Lee; Yun Shan Chew; Choon Bing Low; Vishal Pendharkar; Vithya Manoharan; Susmitha Vuddagiri; Kanda Sangthongpitag; Joma Joy; Alex Matter; Jeffrey Hill; Thomas H. Keller; Klement Foo

doi:10.1021/acsmedchemlett.9b00170

Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

Chuhui Huang
, Si Si Liew
, Grace R. Lin
, Anders Poulsen
, Melgious J.Y. Ang
, Brian C.S. Chia
, Sin Yin Chew
, Zekui P. Kwek
, John L.K. Wee
, Esther H. Ong
, Priya Retna
, Nithya Baburajendran
, Rong Li
, Weixuan Yu
, Xiaoying Koh-Stenta
, Anna Ngo
, Sravanthy Manesh
, Justina Fulwood
, Zhiyuan Ke
, Hwa Hwa Chung

Sugunavathi Sepramaniam, Xin Hui Chew, Nurul Dinie, May Ann Lee, Yun Shan Chew, Choon Bing Low, Vishal Pendharkar, Vithya Manoharan, Susmitha Vuddagiri, Kanda Sangthongpitag, Joma Joy, Alex Matter, Jeffrey Hill, Thomas H. Keller, Klement Foo

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

28 Citations (Scopus)

Abstract

SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3′s enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

Original language	English
Pages (from-to)	978-984
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	10
Issue number	6
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00170
Publication status	Published - 13 Jun 2019
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Covalent
Epigenetics
Irreversible
Methyltransferase

Access to Document

10.1021/acsmedchemlett.9b00170

Cite this

Huang, C., Liew, S. S., Lin, G. R., Poulsen, A., Ang, M. J. Y., Chia, B. C. S., Chew, S. Y., Kwek, Z. P., Wee, J. L. K., Ong, E. H., Retna, P., Baburajendran, N., Li, R., Yu, W., Koh-Stenta, X., Ngo, A., Manesh, S., Fulwood, J., Ke, Z., ... Foo, K. (2019). Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3. ACS Medicinal Chemistry Letters, 10(6), 978-984. https://doi.org/10.1021/acsmedchemlett.9b00170

@article{f42ab44800de4144af0b76a73b36646f,

title = "Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3",

abstract = "SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3′s enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.",

keywords = "Covalent, Epigenetics, Irreversible, Methyltransferase",

author = "Chuhui Huang and Liew, \{Si Si\} and Lin, \{Grace R.\} and Anders Poulsen and Ang, \{Melgious J.Y.\} and Chia, \{Brian C.S.\} and Chew, \{Sin Yin\} and Kwek, \{Zekui P.\} and Wee, \{John L.K.\} and Ong, \{Esther H.\} and Priya Retna and Nithya Baburajendran and Rong Li and Weixuan Yu and Xiaoying Koh-Stenta and Anna Ngo and Sravanthy Manesh and Justina Fulwood and Zhiyuan Ke and Chung, \{Hwa Hwa\} and Sugunavathi Sepramaniam and Chew, \{Xin Hui\} and Nurul Dinie and Lee, \{May Ann\} and Chew, \{Yun Shan\} and Low, \{Choon Bing\} and Vishal Pendharkar and Vithya Manoharan and Susmitha Vuddagiri and Kanda Sangthongpitag and Joma Joy and Alex Matter and Jeffrey Hill and Keller, \{Thomas H.\} and Klement Foo",

note = "Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

year = "2019",

month = jun,

day = "13",

doi = "10.1021/acsmedchemlett.9b00170",

language = "English",

volume = "10",

pages = "978--984",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "6",

}

Huang, C, Liew, SS, Lin, GR, Poulsen, A, Ang, MJY, Chia, BCS, Chew, SY, Kwek, ZP, Wee, JLK, Ong, EH, Retna, P, Baburajendran, N, Li, R, Yu, W, Koh-Stenta, X, Ngo, A, Manesh, S, Fulwood, J, Ke, Z, Chung, HH, Sepramaniam, S, Chew, XH, Dinie, N, Lee, MA, Chew, YS, Low, CB, Pendharkar, V, Manoharan, V, Vuddagiri, S, Sangthongpitag, K, Joy, J, Matter, A, Hill, J, Keller, TH & Foo, K 2019, 'Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3', ACS Medicinal Chemistry Letters, vol. 10, no. 6, pp. 978-984. https://doi.org/10.1021/acsmedchemlett.9b00170

TY - JOUR

T1 - Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

AU - Huang, Chuhui

AU - Liew, Si Si

AU - Lin, Grace R.

AU - Poulsen, Anders

AU - Ang, Melgious J.Y.

AU - Chia, Brian C.S.

AU - Chew, Sin Yin

AU - Kwek, Zekui P.

AU - Wee, John L.K.

AU - Ong, Esther H.

AU - Retna, Priya

AU - Baburajendran, Nithya

AU - Li, Rong

AU - Yu, Weixuan

AU - Koh-Stenta, Xiaoying

AU - Ngo, Anna

AU - Manesh, Sravanthy

AU - Fulwood, Justina

AU - Ke, Zhiyuan

AU - Chung, Hwa Hwa

AU - Sepramaniam, Sugunavathi

AU - Chew, Xin Hui

AU - Dinie, Nurul

AU - Lee, May Ann

AU - Chew, Yun Shan

AU - Low, Choon Bing

AU - Pendharkar, Vishal

AU - Manoharan, Vithya

AU - Vuddagiri, Susmitha

AU - Sangthongpitag, Kanda

AU - Joy, Joma

AU - Matter, Alex

AU - Hill, Jeffrey

AU - Keller, Thomas H.

AU - Foo, Klement

PY - 2019/6/13

Y1 - 2019/6/13

N2 - SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3′s enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

AB - SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4-chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3′s enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

KW - Covalent

KW - Epigenetics

KW - Irreversible

KW - Methyltransferase

UR - https://www.scopus.com/pages/publications/85066490432

U2 - 10.1021/acsmedchemlett.9b00170

DO - 10.1021/acsmedchemlett.9b00170

M3 - Article

AN - SCOPUS:85066490432

SN - 1948-5875

VL - 10

SP - 978

EP - 984

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 6

ER -

Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Erratum: Discovery of irreversible inhibitors targeting histone methyltransferase, SMYD3 (ACS Medicinal Chemistry Letters (2019) 10:6 (978−984) DOI: 10.1021/acsmedchemlett.9b00170)

Cite this