Abstract A11: Therapeutic targeting of GCB- and ABC-DLBCLS by rationally designed BCL6 inhibitors

BCL6公司 癌症研究 生物 心理压抑 体内 遗传学 基因 B细胞 基因表达 抗体 生发中心
作者
Mariano Cárdenas,Wenbo Yu,Wendy Béguelin,Teater R. Matthew,Huimin Geng,Ronald E. Goldstein,Erin Oswald,Katerina Hatzi,Shao-Ning Yang,Joanna S. Cohen,Rita Shaknovich,Kenno Vanommeslaeghe,Huimin Cheng,Dongdong Liang,Hyoje Cho,Joshua M. Abbott,Wayne Tam,John P. Leonard,Leandro Cerchietti,Tomasz Cierpicki,Fengtian Xue,Alexander D. MacKerell,Ari Melnick
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:23 (1_Supplement): A11-A11
标识
DOI:10.1158/1557-3265.pmccavuln16-a11
摘要

Abstract Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands. Citation Format: Mariano Gonzalo Cardenas, Wenbo Yu, Wendy Beguelin, Teater R. Matthew, Huimin Geng, Rebecca Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyoje Cho, Joshua Abbott, Wayne Tam, John P. Leonard, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell, Jr., Ari Melnick. Therapeutic targeting of GCB- and ABC-DLBCLS by rationally designed BCL6 inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A11.
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