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Efficient identification of novel anti-glioma lead compounds by machine learning models.

Abstract：

:Glioblastoma multiforme (GBM) is the most devastating and widespread primary central nervous system tumor. Pharmacological treatment of this malignance is limited by the selective permeability of the blood-brain barrier (BBB) and relies on a single drug, temozolomide (TMZ), thus making the discovery of new compounds challenging and urgent. Therefore, aiming to discover new anti-glioma drugs, we developed robust machine learning models for predicting anti-glioma activity and BBB penetration ability of new compounds. Using these models, we prioritized 41 compounds from our in-house library of compounds, for further in vitro testing against three glioma cell lines and astrocytes. Subsequently, the most potent and selective compounds were resynthesized and tested in vivo using an orthotopic glioma model. This approach revealed two lead candidates, 4m and 4n, which efficiently decreased malignant glioma development in mice, probably by inhibiting thioredoxin reductase activity, as shown by our enzymological assays. Moreover, these two compounds did not promote body weight reduction, death of animals, or altered hematological and toxicological markers, making then good candidates for lead optimization as anti-glioma drug candidates.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Neves BJ,Agnes JP,Gomes MDN,Henriques Donza MR,Gonçalves RM,Delgobo M,Ribeiro de Souza Neto L,Senger MR,Silva-Junior FP,Ferreira SB,Zanotto-Filho A,Andrade CH

doi

10.1016/j.ejmech.2019.111981

subject

Has Abstract

pub_date

2020-03-01 00:00:00

pages

111981

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)31133-X

journal_volume

189

pub_type

杂志文章

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