2. Academic Validation
  3. The novel cereblon modulator CC-885 inhibits mitophagy via selective degradation of BNIP3L

The novel cereblon modulator CC-885 inhibits mitophagy via selective degradation of BNIP3L

  • Acta Pharmacol Sin. 2020 Sep;41(9):1246-1254. doi: 10.1038/s41401-020-0367-9.
Bing-Bing Hao 1 2,  Xiao-Jing Li 3,  Xing-Long Jia 1 4,  Yu-Xing Wang 5,  Lin-Hui Zhai 1 2,  Duan-Zhuo Li 5,  Jie Liu 5,  Die Zhang 5,  Yu-Lu Chen 5,  Yong-Hu Xu 6,  Sang-Kyu Lee 7,  Guo-Feng Xu 6,  Xiao-Hua Chen 2 8,  Yong-Jun Dang 3,  Bin Liu 9,  Min-Jia Tan 10 11
Affiliations

Affiliations

  • 1 The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, 200030, China.
  • 4 Lab for Noncoding RNA and Cancer, School of Life Science, Shanghai University, Shanghai, 200444, China.
  • 5 Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Huangshi, 435003, China.
  • 6 Department of Pediatric Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang St., Shanghai, 200092, China.
  • 7 BK21, Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • 8 Chinese Academy of Sciences Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 9 Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Huangshi, 435003, China. liubin3575630@163.com.
  • 10 The Chemical Proteomics Center and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. mjtan@simm.ac.cn.
  • 11 University of Chinese Academy of Sciences, Beijing, 100049, China. mjtan@simm.ac.cn.
PMID: 32210356 DOI: 10.1038/s41401-020-0367-9
Abstract

Mitophagy is a degradative pathway that mediates the degradation of the entire mitochondria, and defects in this process are implicated in many diseases including Cancer. In mammals, Mitophagy is mediated by BNIP3L (also known as NIX) that is a dual regulator of mitochondrial turnover and programmed cell death pathways. Acute myeloid leukemia (AML) cells with deficiency of BNIP3L are more sensitive to mitochondria-targeting drugs. But small molecular inhibitors for BNIP3L are currently not available. Some immunomodulatory drugs (IMiDs) have been proved by FDA for hematologic malignancies, however, the underlining molecular mechanisms are still elusive, which hindered the applications of BNIP3L inhibition for AML treatment. In this study we carried out MS-based quantitative proteomics analysis to identify the potential neosubstrates of a novel thalidomide derivative CC-885 in A549 cells. In total, we quantified 5029 proteins with 36 downregulated in CRBN+/+ cell after CC-885 administration. Bioinformatic analysis showed that macromitophagy pathway was enriched in the negative pathway after CC-885 treatment. We further found that CC-885 caused both dose- and time-dependent degradation of BNIP3L in CRBN+/+, but not CRBN-/- cell. Thus, our data uncover a novel role of CC-885 in the regulation of Mitophagy by targeting BNIP3L for CRL4CRBN E3 ligase-dependent ubiquitination and degradation, suggesting that CC-885 could be used as a selective BNIP3L degradator for the further investigation. Furthermore, we demonstrated that CC-885 could enhance AML cell sensitivity to the mitochondria-targeting drug rotenone, suggesting that combining CC-885 and mitochondria-targeting drugs may be a therapeutic strategy for AML patients.

Keywords

BNIP3L; CC-885; CRBN; acute myeloid leukemia; immunomodulatory drugs (IMiDs); mitochondria-targeting drugs; mitophagy.

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