Drug discovery of anticancer drugs targeting methylenetetrahydrofolate dehydrogenase 2

Ayumu Asai,Jun Koseki,Masamitsu Konno,Tatsunori Nishimura,Noriko Gotoh,Taroh Satoh,Yuichiro Doki,Masaki Mori,Hideshi Ishii

doi:10.1016/j.heliyon.2018.e01021

Ayumu Asai, Jun Koseki + Show 7 more

Open Access

https://doi.org/10.1016/j.heliyon.2018.e01021

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Journal: Heliyon	Publication Date: Dec 1, 2018
Citations: 24	License type: cc-by

Affiliation: Kanazawa University, Osaka University, Kyushu University

Abstract

Many anticancer drugs have serious adverse effects; therefore, it is necessary to target features specific to cancer cells to minimize the effects on healthy cells. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was reported to be specifically enhanced in cancer. We confirmed the validity of MTHFD2 as a drug discovery target using clinical data. In addition, we performed in silico screening to design an anticancer drug specifically targeting MTHFD2. Analysis of the clinical data indicated that MTHFD2 was enhanced in most cancers compared with normal tissues, and affected the prognosis in cancer patients. Candidate compounds for MTHFD2 inhibitors were identified using in silico drug discovery techniques, and the important interactions for MTHFD2 binding were determined. In addition, these candidate compounds decreased levels of MTHFD2 metabolites in cancer cells. The findings of the present study may help to develop anticancer drugs targeting MTHFD2, with a view to minimizing the adverse effects of anticancer drugs.

Highlights

Various anticancer drugs have been designed for cancer therapy
methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression was compared between primary tumor and normal tissue in various cancers using The Cancer Genome Atlas (TCGA) data to determine the specificity of MTHFD2 in cancer cells
Metabolism is crucial for cell survival, and differs greatly between cancer cells and normal cells [6]

Summary

Introduction

Various anticancer drugs have been designed for cancer therapy. Anticancer drugs directly targeting DNA replication and cell division, such as alkylating agents, topoisomerase inhibitors, and antimicrotubule agents, have serious effects on cancer cells as well as normal cells [1, 2, 3]. Targeting features that are specific to cancer cells can minimize the effects on normal cells. Antibody drugs have attracted attention, since they have a high specificity to cancer cells. These drugs present problems such as not being able to access intracellular targets [4]. Inexpensive low molecular weight anticancer drugs specific to cancer cells are required for multidrug combination chemotherapy

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