The MAPK-activated protein kinase 2 (MK2) inhibitor CMPD1 is a novel microtubule targeting agent for glioblastoma therapy

F. Gurgis, M. Åkerfeldt, C. Wong, B. Heng, G. J. Guillemin, M. Chircop, L. Munoz

Research output: Contribution to journalMeeting abstract

6 Citations (Scopus)

Abstract

Introduction
Glioblastoma is among the most lethal and least successfully treated solid tumours. A suitable agent for brain tumour treatment must cross the blood-brain barrier and lack neurotoxicity. MAPK-activated protein kinase 2 (MK2) is a cell cycle checkpoint kinase involved in DNA damage response. MK2 inhibitors enhance efficacy of conventional chemotherapeutic agents, but their effectiveness as a single agent has not been investigated.

Material and Methods
The anti-cancer effectiveness of an MK2a substrate-selective p38 inhibitor CMPD1 (Boehringer-Ingelheim; Davidson et. al., Biochemistry 2004; 43(37):11658-71) was determined in a panel of glioblastoma cell lines and normal cells (primary human microglia, astrocytes and neurons) using cell viability, Annexin-V staining and cell cycle analysis. Immunofluorescence and tubulin polymerization assays were conducted to study the effect of CMPD1 on microtubules.

Results
The MK2 inhibitor CMPD1 demonstrated single agent anti-cancer efficacy with a submicro-molar IC50 in glioblastoma cells yet exhibited minimal toxicity on normal cells. Treatment of U87 cells with CMPD1 resulted in G2/M arrest and accumulation of a polyploid (>4n) population. Moreover, CMPD1 induced apoptosis and affected the expression of anti-apoptotic proteins in glioblastoma cells. However, these observations were less evident in primary astrocytes. Interestingly, while reported to be MK2a substrate-selective p38 inhibitor, CMPD1 did not inhibit MK2 or its downstream target Hsp27 at doses that are cytotoxic in U87 cells. siRNA knockdown of MK2 did not alter the IC50 of CMPD1 suggesting that MK2 is not involved in cell death. Instead, we identified CMPD1 as a tubulin depolymerizing agent causing microtubule disruption in glioblastoma cells. Furthermore, we discovered that CMPD1 reduces the expression of tubulin in U87 cells and inhibited the self-renewal capacity of glioblastoma cells.

Conclusions
Collectively, we have discovered a novel microtubule targeting drug candidate with selective toxicity for glioblastoma therapy. We are currently developing analogues with enhanced blood-brain barrier permeable properties.
Original languageEnglish
Pages (from-to)e114
Number of pages1
JournalClinical Therapeutics
Volume37
Issue number8 Supplement
DOIs
Publication statusPublished - Aug 2015
Event12th Congress of the European-Association-for-Clinical-Pharmacology-and-Therapeutics - Madrid, Spain
Duration: 27 Jun 201530 Jun 2015

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