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

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.
PMID: 32210356 [PubMed - as supplied by publisher]

Source: Acta Pharmacologica Sinica - March 23, 2020 Category: Drugs & Pharmacology Authors: Hao BB, Li XJ, Jia XL, Wang YX, Zhai LH, Li DZ, Liu J, Zhang D, Chen YL, Xu YH, Lee SK, Xu GF, Chen XH, Dang YJ, Liu B, Tan MJ Tags: Acta Pharmacol Sin Source Type: research