OBJECTIVES: Two 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. METHODS: Sixteen 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. RESULTS: The 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. CONCLUSIONS: The dual inhibition of BET and CBP/EP300 has potential therapeutic benefits for patients with MM.
OBJECTIVES: Two 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. METHODS: Sixteen 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. RESULTS: The 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. CONCLUSIONS: The dual inhibition of BET and CBP/EP300 has potential therapeutic benefits for patients with MM.
Authors: Lu Feng; Guan Wang; Yi Chen; Gu He; Bo Liu; Jie Liu; Cheng-Ming Chiang; Liang Ouyang Journal: Med Res Rev Date: 2021-10-11 Impact factor: 12.944
Authors: Miranda Fernández-Serrano; René Winkler; Juliana C Santos; Marguerite-Marie Le Pannérer; Marcus Buschbeck; Gaël Roué Journal: Int J Mol Sci Date: 2021-12-27 Impact factor: 5.923
Authors: Noortje van Gils; Tania Martiañez Canales; Eline Vermue; Arjo Rutten; Fedor Denkers; Tiem van der Deure; Gert J Ossenkoppele; Francis Giles; Linda Smit Journal: Hemasphere Date: 2021-07-08
Authors: Katiri J Snyder; Hannah K Choe; Yandi Gao; Natalie E Sell; Kara M Braunreiter; Nina C Zitzer; Lotus Neidemire-Colley; Sonu Kalyan; Adrienne M Dorrance; Andrea Keller; Maria M Mihaylova; Satishkumar Singh; Lalit Sehgal; Gideon Bollag; Yan Ma; Ben Powell; Steven M Devine; Parvathi Ranganathan Journal: Front Oncol Date: 2021-10-15 Impact factor: 6.244