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.
Natasha C Lucki  1 ,  Genaro R Villa  2  3 ,  Naja Vergani  1  4 ,  Michael J Bollong  4 ,  Brittney A Beyer  1  4 ,  Jae Wook Lee  4  5 ,  Justin L Anglin  1 ,  Stephan H Spangenberg  4 ,  Emily N Chin  4 ,  Amandeep Sharma  4 ,  Kevin Johnson  6 ,  Philipp N Sander  4 ,  Perry Gordon  6 ,  Stephen L Skirboll  7 ,  Heiko Wurdak  8 ,  Peter G Schultz  9  4 ,  Paul S Mischel  10 ,  Luke L Lairson  11
Affiliations
  • 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; [email protected] [email protected] [email protected].
  • 10. Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093; [email protected] [email protected] [email protected].
  • 11. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; [email protected] [email protected] [email protected].
PMID: 30846550 DOI: 10.1073/pnas.1816626116
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.
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