An Enolase Inhibitor for the Targeted Treatment of ENO1-deleted Cancers

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2020 Nov 24

PMID 33230295

Citations 37

Authors

Yu-Hsi Lin

Nikunj Satani

Naima Hammoudi

Victoria C Yan

Yasaman Barekatain

Sunada Khadka

Jeffrey J Ackroyd

Dimitra K Georgiou

Cong-Dat Pham

Kenisha Arthur

David Maxwell

Zhenghong Peng

Paul G Leonard

Barbara Czako

Federica Pisaneschi

Pijus Mandal

Yuting Sun

Rafal Zielinski

Susana Castro Pando

Xiaobo Wang

Theresa Tran

Quanyu Xu

Qi Wu

Yongying Jiang

Zhijun Kang

John M Asara

Waldemar Priebe

William Bornmann

Joseph R Marszalek

Ronald A DePinho

Florian L Muller

Affiliations

Soon will be listed here.

Abstract

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.

Citing Articles

Natural product mediated mesenchymal-epithelial remodeling by covalently binding ENO1 to degrade m6A modified -catenin mRNA.

Chen T, Liu G, Chen S, Zhang F, Ma S, Bai Y Acta Pharm Sin B. 2025; 15(1):467-483.

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Role of ENO1 and its targeted therapy in tumors.

Li Y, Liu L, Li B J Transl Med. 2024; 22(1):1025.

PMID: 39543641 PMC: 11566422. DOI: 10.1186/s12967-024-05847-8.

Histone lactylation drives CD8 T cell metabolism and function.

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PMID: 39375549 DOI: 10.1038/s41590-024-01985-9.

Towards next-generation treatment options to combat Plasmodium falciparum malaria.

Okombo J, Fidock D Nat Rev Microbiol. 2024; 23(3):178-191.

PMID: 39367132 PMC: 11832322. DOI: 10.1038/s41579-024-01099-x.

Enolase inhibitors as therapeutic leads for Naegleria fowleri infection.

Milanes J, Yan V, Pham C, Muller F, Kwain S, Rees K PLoS Pathog. 2024; 20(8):e1012412.

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