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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Astrocytes
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Delivery Systems
  • Drug Evaluation, Preclinical
  • Female
  • Glioblastoma
  • Heterografts
  • High-Throughput Screening Assays
  • Humans
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Pyroptosis / drug effects
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk2 protein, mouse
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7