NEO2734

NEO2734 is a dual inhibitor of the bromodomain and extra terminal domain family of proteins (BET) and p300/CREB-binding protein (CBP).¹ It binds to bromodomain-containing protein 2 (BRD2), BRD3, and BRD4 (K_ds = 3.2, 2.3, and 6.5 nM, respectively), bromodomain testis-specific protein 1 (BRDT1) and BRDT2 (K_ds = 3.1 and 25 nM, respectively), and p300 and CBP (K_ds = 25 and 23 nM, respectively). NEO2734 inhibits the growth of DU145 prostate cancer cells (IC₅₀ = 1.08 µM) and DU145 cells containing the E3 ubiquitin ligase adapter protein speckle-type POZ protein (SPOP) with a glutamine-to-proline mutation at position 165 (SPOP^Q165P; IC₅₀ = 0.69 µM).² It also reduces tumor growth, as well as intratumoral levels of prostate-specific antigen (PSA), in prostate cancer patient-derived xenograft (PDX) mouse models expressing either wild-type SPOP or SPOP^Q165P when administered at a dose of 30 mg/kg.

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1. Giles, F.J. Treatment of bet inhibitor-resistant cancers and other diseases responsive to dual bet and CBP/EP300 inhibition therapy. (2020).

2. Yan, Y., Ma, J., Wang, D., et al. The novel BET-CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild-type prostate cancer. EMBO Mol. Med. 7(11), e10659 (2019).