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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 37634473 DOI: 10.1016/j.biopha.2023.115358
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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