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Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6435-6440. doi: 10.1073/pnas.1816626116. Epub 2019 Mar 7.

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

Author information

1
California Institute for Biomedical Research, La Jolla, CA 92037.
2
Department of Molecular and Medical Pharmacology, Medical Scientist Training Program, David Geffen UCLA School of Medicine, Los Angeles, CA 90095.
3
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093.
4
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
5
Natural Constituents Research Center, Korea Institute of Science and Technology, Gangneung, 25451 Gangwon-do, South Korea.
6
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
7
Department of Neurosurgery, Section of Neurosurgery, Veterans Affairs Palo Alto Health Care System, Stanford University, Palo Alto, CA 94304.
8
Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital, LS9 7TF Leeds, United Kingdom.
9
California Institute for Biomedical Research, La Jolla, CA 92037; schultz@scripps.edu pmischel@ucsd.edu llairson@scripps.edu.
10
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093; schultz@scripps.edu pmischel@ucsd.edu llairson@scripps.edu.
11
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; schultz@scripps.edu pmischel@ucsd.edu llairson@scripps.edu.

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.

KEYWORDS:

chemical genetics; glioblastoma; phenotypic drug screening; receptor-interacting protein kinase 2; target identification

PMID:
30846550
PMCID:
PMC6442583
DOI:
10.1073/pnas.1816626116
[Indexed for MEDLINE]
Free PMC Article

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