Novel synthetic tosyl chloride-berbamine regresses lethal MYC-positive leukemia by targeting CaMKIIγ/Myc axis

• Published in: Biomedicine & pharmacotherapy Vol. 117; p. 109134
• Main Authors: Yu, Qingfeng, Wang, Ping, Yang, Linlin, Wu, Zhaoxing, Li, Shu, Xu, Ying, Wu, Bowen, Ma, An, Gan, Xiaoxian, Xu, Rongzhen
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-09-2019; Elsevier
• Subjects: Acute leukemia; Administration, Oral; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Benzylisoquinolines - administration & dosage; Benzylisoquinolines - chemistry; Benzylisoquinolines - pharmacology; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; CaMKIIγ; Cell Line, Tumor; Cell Proliferation - drug effects; Gene Expression Regulation, Leukemic - drug effects; Humans; Inhibitory Concentration 50; Leukemia - enzymology; Leukemia - pathology; Mice; MYC; Proto-Oncogene Proteins c-myc - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Tosyl chloride-berbamine; Tosyl Compounds - administration & dosage; Tosyl Compounds - chemistry; Tosyl Compounds - pharmacology; Transcription, Genetic - drug effects; t(9;22); BC; ALL; Tosyl chloride-berbamine; trisomy 13; trisomy 11; t(8;16); t(1;3); abn(3q); MPP; Complex; CaMKIIγ; MYC; t(11q23)/MLL; 9q; HSC; del(7q)/7q; nan; early_PM; Complex_ del(5q); MDS; Trisomy 8; MM; t(9;11); 5/7(q); t(15;17); CMP; Late_PM; Mono; Acute leukemia; GMP; MY; Normal; PMN; inv; Complex_ untypical; t(8;21); t(6;9); 7; 8; MEP; del(9q); del(5q); Other
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.109134

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Proto-oncogene Myc, a key transcription factor, is frequently deregulated in human leukemia with aggressive and poor clinical outcome, but the development of MYC inhibitors remains challenging due to MYC helix-loop-helix topology lacking druggable domains. Here we describe a novel oral active small molecule analog of berbamine, tosyl chloride-berbamine (TCB), that efficiently eliminates MYC-positive leukemia in vitro and in vivo. Mechanistically, TCB potently reduced MYC protein by inhibiting CaMKIIγ, a critical enzyme that stabilizes MYC protein, and induces apoptosis of MYC-positive leukemia cells. In vivo, oral administration of TCB markedly eliminated lethal MYC-positive acute lymphoblastic leukemia (ALL) with well tolerability in orthotopic mouse model. Our studies identify CaMKIIγ/Myc axis as a valid target for developing small molecule-based new therapies for treating MYC-mediated leukemia and demonstrate that TCB is an orally active analog of berbamine that kills MYC-positive leukemia cells.