1. Academic Validation
  2. A small molecule BCL6 inhibitor as chemosensitizers in acute myeloid leukemia

A small molecule BCL6 inhibitor as chemosensitizers in acute myeloid leukemia

  • Biomed Pharmacother. 2023 Oct;166:115358. doi: 10.1016/j.biopha.2023.115358.
Lin Zhang 1 Min Wu 1 Weikai Guo 1 Shuangshuang Zhu 1 Shen Li 1 Shiyi Lv 1 Yan Li 1 Layang Liu 1 Yajing Xing 1 Huang Chen 1 Mingyao Liu 1 Shihong Peng 2 Yihua Chen 3 Zhengfang Yi 4
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dong Chuan Rd, Shanghai 200241, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dong Chuan Rd, Shanghai 200241, China; Shanghai Yuyao Biotech Co., Ltd., Shanghai 200241, China. Electronic address: shihong.peng9001@gmail.com.
  • 3 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dong Chuan Rd, Shanghai 200241, China. Electronic address: yhchen@bio.ecnu.edu.cn.
  • 4 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dong Chuan Rd, Shanghai 200241, China. Electronic address: zfyi@bio.ecnu.edu.cn.
Abstract

BCL6 is a transcriptional repressor that regulates multiple genes involved in immune cell differentiation, DNA damage repair, cell cycle, and Apoptosis, and is a carcinogenic factor in acute myeloid leukemia (AML). AML is one of the four major types of leukemia with the 5-year survival rate of patients is less than 20% and chemotherapy resistance remains the major obstacle to the treatment failure of AML. We identified WK499, a small molecule compound that can bind to BCL6BTB structure. Treatment with WK499 hinders the interactions between BCL6 with its corepressor proteins, resulting in a remarkable change of BCL6 downstream genes and anti-proliferative effects in AML cells, and inducing cell cycle arrest and Apoptosis. We verified that AraC and DOXo could induce BCL6 expression in AML cells, and found that WK499 had a synergistic effect when combined with chemotherapeutic drugs. We further proved that WK499 and AraC could achieve a better result of inhibiting the growth of AML in vivo. These findings indicate that WK499, a small molecule inhibitor of BCL6, not only inhibits the proliferation of AML, but also provides an effective therapeutic strategy for increasing AML sensitivity to chemotherapy.

Keywords

AML; BCL6; Chemosensitizer; Combination therapy.

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