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EG‐011 IS A NOVEL SMALL MOLECULE WITH IN VITRO AND IN VIVO ANTI‐TUMOR ACTIVITY AGAINST LYMPHOMA

Background: Lymphoma cells have frequent deregulation of their epigenome. The Bromodomain (BRD) and Extra-Terminal domain (BET) proteins are key regulators of the transcription process. The acetyltransferases cyclic AMP response element binding protein (CREB)-binding protein (CBP) and the E1A interacting protein of 300 kDa (EP300) are highly homologous BRD-containing transcriptional co-activators and are often mutated in diffuse large B cell lymphoma (DLBCL). Targeting the individual classes of proteins is a new therapeutic approach, as shown especially by BET inhibitors with both preclinical and early clinical anti-lymphoma activity. NEO2734 and NEO1132 are novel oral dual inhibitors of BET and CREBBP/EP300 proteins. Here, we present data exploring their anti-tumor activity in DLBCL models. Methods: Lymphoma cell lines were exposed to increasing doses of compounds for 72h. Cell proliferation was measured with the MTT assay. Results: Twenty-seven DLBCL cell lines were exposed to NEO2734 and NEO1132. NEO2734 showed anti-tumor activity with a median IC50 of 157 nM (95% C.I., 135-214), while NEO1132 showed a lower activity compared, with a median IC50 of 400nM (95% C.I., 316-622). For both compounds, cell lines derived from activated B-cell–like (ABC) DLBCL (n.=8) were more sensitive than the ones derived from germinal center B-cell (GCB) DLBCL (n.=19) (P < 0.05). All the cell lines were also exposed to a BET inhibitor (birabresib, OTX015) and to a CREBBP/EP300 inhibitor (CBP30). The median IC50 values of the 2 molecules were 237 nM (95% C.I., 171-344) and 5.5 μM (95% C.I., 4.2-8.3 μM) respectively. The 4 compounds presented a similar pattern of anti-proliferative activity across all the cell lines (p < 0.001) (NEO2734 vs NEO1132, r = 0.99; NEO2734 vs birabresib: r =0.97; NEO2734 vs CBP30, r = 0.87; birabresib vs CBP30, r = 0.85) but with different degrees of IC50. NEO2734 was more potent (P < 0.05) than birabresib, CBP30 and NEO1132. The higher activity of NEO2734 compared to NEO1132 could be explained by its superior potency in binding CREBBP and EP300. Cell cycle demonstrates that NEO2734 has a cytotoxic activity in 4 out of 5 cell lines tested (3 ABC and 2 GCB-DLBCL) and a slightly higher activity than birabresib in 2 cell lines. Transcriptome profiling on 2 GCBand 2 ABC-DLBCLs treated for 6h with NEO2734 or birabresib highlighted a very similar effect of the two compounds (r= 0.90, P < 0.001), but also highlighted changes specifically induced by the dual inhibitor. Conclusions: The novel dual BET and CREBBP/EP300 inhibitors NEO2734 and NEO1132 showed robust in vitro anti-tumor activity in DLBCL cell lines. Transcriptome changes and antiproliferative activity demonstrated both some overlap between NEO2734 and birabresib but also distinct features of the dual inhibition approach.