Dual Bromodomain Inhibitors NEO1132 and NEO2734: A Comparative Study on Anti-Tumor Activity in Diffuse Large B Cell Lymphoma

Lymphoma cells often have an altered epigenome, and the Bromodomain and Extra-Terminal (BET) proteins, along with CREB-binding protein (CBP) and E1A interacting protein of 300 kDa (EP300), play essential roles in transcription regulation. BET inhibitors have shown promise in combating lymphoma, and dual inhibitors targeting both BET and CREBBP/EP300 are being explored for their potential therapeutic effects.

NEO2734 and NEO1132 are newly developed, chemically distinct dual inhibitors of BET, CREBBP, and EP300 proteins, with varying affinities for their targets. An evaluation of their anti-tumor activity in diffuse large B cell lymphoma (DLBCL) models revealed that NEO2734 was significantly more potent than NEO1132, with a median IC50 of 157 nM compared to NEO1132's 400 nM. The activity of both compounds was more pronounced in cell lines derived from the activated B-cell-like (ABC) subtype of DLBCL than those from the germinal center B-cell (GCB) subtype.

The study also compared the dual inhibitors to a BET inhibitor (birabresib, OTX015) and a CREBBP/EP300 inhibitor (CBP30). NEO2734 was found to be more potent than birabresib, CBP30, and NEO1132, suggesting that its higher activity may be due to its greater binding affinity for CREBBP and EP300. This finding underscores the significance of simultaneous BET/CREBBP/EP300 inhibition.

In summary, the novel dual BET and CREBBP/EP300 inhibitors NEO2734 and NEO1132 have demonstrated substantial in vitro anti-tumor activity across a broad range of DLBCL cell lines. Their efficacy appears to correlate with their binding affinity for both BET and CREBBP/EP300 proteins, indicating a promising direction for the development of therapies targeting these proteins in DLBCL.