Epigenetic mechanisms are emerging as attractive therapeutic targets in solid tumors and epigenetic drugs are already being tested in HCC clinical trials. However, the extensive functional crosstalk between chromatin marks such as DNA and H3K9 methylation, suggests that simultaneous targeting of different epigenetic modifiers may improve therapeutic efficacy. We recently demonstrated this contention by showing the remarkable antitumoral activity of CM-272, a dual G9a/DNMT1 inhibitor, in different hematological neoplasms. Now we provide evidence supporting the potential of combined G9a/DNMT1 antagonism for HCC treatment.
First, we demonstrated the coordinated overexpression of G9a and DNMT1, along with their key adaptor UHRF1, in human HCC tissues. The pathophysiological relevance of this matched overexpression is suggested by its significant association with molecular, histological and clinical characteristics indicative of aggressive disease and poor prognosis. The rationale for the simultaneous inhibition of G9a/DNMT1 in HCC was further established by the synergistic anti-proliferative action of combined G9a and DNMT1 specific antagonists. Thus, CM-272 exerted a very potent antiproliferative effect in a wide panel of human HCC cell lines, which also showed a
close correlation in the expression of G9a, DNMT1 and the UHRF1 adaptor. CM-272 inhibited HCC cells growth in vivo in the absence of apparent toxicity. The high specificity of CM-272 for G9a/DNMT1, and a mechanism of action based on the reversible inhibition of G9a and DNMT1 binding to their substrates, but not to Sadenosylmethionine, may contribute to explain its lack of off-target effects and systemic toxicity.
A patent application for the small molecules mentioned in this project was initially filed (June 2014), covering chemical series for these compounds and finally accepted (Agirre, X. et al. Novel compounds as dual inhibitors of histone methyltransferases and DNA methyltransferases. WO2015192981A1, 30 March (2015). Any potential new application derived of these findings will be also susceptible to be protected from IP perspective. If the output of this research is amenable for industrial development it will be readily transferred to interested companies, with positive repercussions for the advancement of this research line, the university's wealth and the scientific and patient’s community at large.
