Glioblastoma multiforme (GBM) is the most malignant form of brain cancer in adults with a very poor prognosis despite treatment. [1] The development of novel therapies for GBM is challenging due to its infiltrative nature, the heterogeneous and adaptive/drug-resistant character of GBM cells, and the blood brain barrier. [2] We discovered that the brain-penetrable small molecule KHS101 [3] selectively induces the self-destruction of molecularly-diverse, human patient-derived GBM cells by targeting specific metabolic vulnerabilities. Moreover, KHS101 is effective in orthotopic xenograft models.
We identified the molecular target of KHS101 in GBMs through a combination of gene expression profiling/‘connectivity mapping’, metabolomics, and chemical proteomics. For the latter, we used a biologically active photo-reactive benzophenone probe (KHS101-BP). Photocrosslinking experiments using KHS101 BP in life cells allowed us to identify a molecular target with direct relevance to KHS101-induced GBM self-destruction. We subsequently developed KHS101 analogues and derivatives incorporating biotin or a fluorophore to enable biophysical characterisation of the interaction between KHS101 and its protein target. These tools may allow the development of assays for rapid screening/optimisation of new compounds for the treatment of GBM.
[1] M. Preusser, S. De Ribaupierre, A. Wohrer, S. C. Erridge, Monika Hegi, M. Weller, and R. Stupp, Neurol. Prog., 2011, 70, 9–21.
[2] S. K. Carlsson, S. P. Brothers, and C. Wahlestedt, EMBO Mol. Med., 2014, 6, 1359–1370.
[3] H. Wurdak, S. Zhu, K. Hoon, L. Aimone, L. L. Lairson, and J. Watson, Proc. Natl. Acad. Sci. U.S.A., 2010, 107, 16542–22360
