2. Academic Validation
  3. Discovery of a potent histone deacetylase (HDAC) 3/6 selective dual inhibitor

Discovery of a potent histone deacetylase (HDAC) 3/6 selective dual inhibitor

  • Eur J Med Chem. 2019 Dec 15:184:111755. doi: 10.1016/j.ejmech.2019.111755.
Uttara Soumyanarayanan 1,  Pondy Murugappan Ramanujulu 2,  Nurulhuda Mustafa 3,  Shozeb Haider 4,  Adina Huey Fang Nee 5,  Jie Xin Tong 6,  Kevin S W Tan 6,  Wee Joo Chng 7,  Brian W Dymock 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
  • 2 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore; Life Sciences Institute, Centre for Life Sciences Level 5, 28 Medical Drive, National University of Singapore, 117456, Singapore.
  • 3 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 10, 119228 Singapore.
  • 4 UCL School of Pharmacy, 29-39 Brunswick Square, Bloomsbury, London, WC1N 1AX, UK.
  • 5 Cancer Science Institute, National University of Singapore, Singapore.
  • 6 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, 5 Science Drive 2, 117545, Singapore.
  • 7 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 10, 119228 Singapore; Cancer Science Institute, National University of Singapore, Singapore; National University Cancer Institute of Singapore, National University Health System, Singapore.
  • 8 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Singapore. Electronic address: bwdnus@gmail.com.
PMID: 31627059 DOI: 10.1016/j.ejmech.2019.111755
Abstract

Herein, we report the discovery of a dual histone deacetylase inhibitor displaying a unique HDAC3/6 selectivity profile. An initial strategy to merge two epigenetic pharmacophores resulted in the discovery of potent HDAC6 inhibitors with selectivity over HDAC1. Screening in an HDAC panel revealed additional low nanomolar inhibition only against HDAC3. Low micromolar antiproliferative activities against two breast Cancer and four hematological Cancer cell lines was supported by pharmacodynamic studies on a preferred molecule, 24c, substantiating the HDAC inhibitory profile in cells. Apoptosis was identified as one of the main cell death pathways. Modelling studies of 24c against HDAC1,2,3 and 6 further provided insights on the orientation of specific residues relevant to compound potency, explaining the observed HDAC3/6 selectivity. A subset of the compounds also exhibited good antimalarial activities, particularly against the chloroquine-resistant strain K1 of P.falciparum. In vitro studies revealed a favourable DMPK profile warranting further investigation of the therapeutic potential of these compounds.

Keywords

Anticancer; Antimalarial; Selective histone deacetylase inhibitor.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z