AbstractObjectivesTwo promising epigenetic therapeutic targets have emerged for the treatment of hematologic malignancies, BET and CBP/EP300 proteins. Several studies have shown that targeting these individual classes of proteins has anti‐tumor activity in multiple myeloma (MM), as well as other cancers. Here, we present the first data exploring the anti‐tumor activity of two novel dual inhibitors, NEO2734 and NEO1132, of both BET and CBP/EP300 proteins in MM.MethodsSixteen MM cell lines (MMCLs) were treated with the dual inhibitors NEO2734 and NEO1132, the single BET inhibitors JQ1, OTX015, IBET‐762, and IBET‐151, and a single CBP/EP300 inhibitor CPI‐637.ResultsThe dual inhibitor NEO2734 showed strong anti‐tumor activity and was consistently highly active against all MMCLs, being as potent as JQ1 and more so than other single inhibitors. NEO2734 and NEO11132 induced a significant G1 cell cycle arrest and decreased c‐MYC and IRF4 protein levels in MMCLs compared to the other single inhibitors. Sensitivity to the dual inhibitors was not dependent on a specific MM molecular subgroup but correlated with c‐MYC protein expression levels.ConclusionsThe dual inhibition of BET and CBP/EP300 has potential therapeutic benefits for patients with MM.

HemaSphere

The Novel Oral BET-CBP/p300 Dual Inhibitor NEO2734 Is Highly Effective in Eradicating Acute Myeloid Leukemia Blasts and Stem/Progenitor Cells

Article

作者: van der Deure, Tiem ; Ossenkoppele, Gert J ; Vermue, Eline ; Giles, Francis ; Martiañez Canales, Tania ; Smit, Linda ; van Gils, Noortje ; Denkers, Fedor ; Rutten, Arjo

Acute myeloid leukemia (AML) is a disease characterized by transcriptional dysregulation that results in a block in differentiation and aberrant self-renewal. Inhibitors directed to epigenetic modifiers, aiming at transcriptional reprogramming of AML cells, are currently in clinical trials for AML patients. Several of these inhibitors target bromodomain and extraterminal domain (BET) proteins, cyclic AMP response binding protein-binding protein (CBP), and the E1A-interacting protein of 300 kDa (p300), affecting histone acetylation. Unfortunately, single epigenetic inhibitors showed limited efficacy due to appearance of resistance and lack of effective eradication of leukemic stem cells. Here, we describe the efficacy of 2 novel, orally available inhibitors targeting both the BET and CBP/p300 proteins, NEO1132 and NEO2734, in primary AML. NEO2734 and NEO1132 efficiently reduced the viability of AML cell lines and primary AML cells by inducing apoptosis. Importantly, both NEO drugs eliminated leukemic stem/progenitor cells from AML patient samples, and NEO2734 increased the effectiveness of combination chemotherapy treatment in an in vivo AML patient-derived mouse model. Thus, dual inhibition of BET and CBP/p300 using NEO2734 is a promising therapeutic strategy for AML patients, making it a focus for clinical translation.

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适应症	最高研发状态	国家/地区	公司	日期
弥漫性大B细胞淋巴瘤	临床前	-	Neomed Institute	-
弥漫性大B细胞淋巴瘤	临床前	-	Biomodal Ltd.	-
白血病	临床前	-	Neomed Institute	-
前列腺癌	临床前	-	Neomed Institute	-