Session: 802. Chemical Biology and Experimental Therapeutics: Poster III
Hematology Disease Topics & Pathways:
Results: JBI-802 shows an IC50 of ~0.05 µM for LSD1 and ~ 0.01 µM for HDAC6 and a strong dose-dependent modulation of biomarkers specific for both these targets. JBI-802 showed anti-proliferative activity against a panel of haematological cancers with EC50 ranging from 0.01 to 0.3 µM. Co-immunoprecipitation studies clearly showed that in addition to HDAC1, HDAC6 also co-immuno-precipitated with LSD1 suggesting that HDAC6 is a part of the CoREST complex. These findings also correlated well with stronger biomarker modulation of some key proteins by JBI-802, in comparison with the single agent LSD1 or HDAC6 selective inhibitors. Additional genomic and transcriptome based studies analyses led to the identification of a biomarker that is specific for dual inhibition. Interestingly, neither LSD1 nor HDAC6 inhibition alone lead to the modulation of this specific biomarker, which was observed only in cell lines that were sensitive to the dual inhibitor. These studies not only pave way for patient stratification in the clinic, but also could be a robust biomarker for treatment response. Data generated so far highlight the promise of this dual inhibitor in several heamatological cancers and more specifically in neoplasms with certain gain-of-function mutations. JBI-802 has optimal oral exposure and has been tested in multiple animal models by oral administration. Consistently, it showed superior efficacy in these models as compared to single agent inhibitors. Exploratory toxicity studies have clearly demonstrated that JBI-802 has an excellent safety profile.
Conclusion: JBI-802 is currently being evaluated in IND-enabling studies to be progressed into clinical trials and such inhibitors could serve as powerful therapeutic agents for the treatment of specific cancers.
Disclosures: No relevant conflicts of interest to declare.
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