CN470 is a BET/CBP/p300 multi-bromodomain inhibitor and has an anti-tumor activity against MLL-rearranged acute lymphoblastic leukemia

• DOI: 10.1016/j.bbrc.2021.12.078
• Publication Date: 2021-12-24T01:36:55Z
• Authors: Natsuki Imayoshi; Makoto Yoshioka; Kuniaki Tanaka; Shyh-Ming Yang; Koshi Akahane; Yuki Toda; Shigekuni Hosogi; Takeshi Inukai; Seiji Okada; David J. Maloney; Tatsutoshi Nakahata; Junko Takita; Itaru Kato; Eishi Ashihara
• Keywords: Gene Rearrangement; 0301 basic medicine; 0303 health sciences; Gene Expression Regulation, Leukemic; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Histone-Lysine N-Methyltransferase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Analysis; Xenograft Model Antitumor Assays; 3. Good health; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; RNA, Messenger; E1A-Associated p300 Protein; Myeloid-Lymphoid Leukemia Protein; Cell Proliferation

Acute lymphoblastic leukemia with chromosomal rearrangements involving the mixed-lineage leukemia (MLL) gene (MLL-r ALL) remains an incurable disease. Thus, development of a safe and effective therapeutic agent to treat this disease is crucial to address this unmet medical need. BRD4, a member of the bromodomain and extra-terminal domain (BET) protein family, and cyclic AMP response element binding protein binding protein (CBP) and p300, two paralogous histone acetyltransferases, are all considered cancer drug targets and simultaneous targeting of these proteins may have therapeutic advantages. Here, we demonstrate that a BET/CBP/p300 multi-bromodomain inhibitor, CN470, has anti-tumor activity against MLL-r ALL in vitro and in vivo. CN470, potently inhibited ligand binding to the bromodomains of BRD4, CBP, and p300 and suppressed the growth of MLL-r ALL cell lines and patient-derived cells with MLL rearrangements. CN470 suppressed mRNA and protein expression of MYC and induced apoptosis in MLL-r ALL cells, following a cell cycle arrest in the G1 phase. Moreover, CN470 reduced BRD4 binding to acetylated histone H3. The in vivo effects of CN470 were investigated using SEMLuc/GFP cells expressing luminescent markers in an orthotopic mouse model. Mice administered CN470 daily had prolonged survival compared to the vehicle group. Further, CN470 also showed anti-tumor effects against an MLL-r ALL patient-derived xenograft model. These findings suggest that inhibition of BET/CBP/p300 by the multi-bromodomain inhibitor, CN470, represents a promising therapeutic approach against MLL-r ALL.