A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer.

Abstract:

:Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

authors

Lucki NC,Villa GR,Vergani N,Bollong MJ,Beyer BA,Lee JW,Anglin JL,Spangenberg SH,Chin EN,Sharma A,Johnson K,Sander PN,Gordon P,Skirboll SL,Wurdak H,Schultz PG,Mischel PS,Lairson LL

doi

10.1073/pnas.1816626116

subject

Has Abstract

pub_date

2019-03-26 00:00:00

pages

6435-6440

issue

13

eissn

0027-8424

issn

1091-6490

pii

1816626116

journal_volume

116

pub_type

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