RRC ID 48850
Author Kurdi A, Cleenewerck M, Vangestel C, Lyssens S, Declercq W, Timmermans JP, Stroobants S, Augustyns K, De Meyer GRY, Van Der Veken P, Martinet W.
Title ATG4B inhibitors with a benzotropolone core structure block autophagy and augment efficiency of chemotherapy in mice.
Journal Biochem. Pharmacol.
Abstract Autophagy is a cell survival mechanism hijacked by advanced tumors to endure a rough microenvironment. Late autophagy inhibitors such as (hydroxy)chloroquine have been used clinically to halt tumor progression with modest success. However, given the toxic nature of these compounds and their lack of specificity, novel targets should be considered. We recently identified a benzotropolone derivative that significantly inhibited the essential autophagy protein ATG4B. Therefore, we synthesized and tested additional benzotropolone compounds to identify a promising ATG4B inhibitor that impairs autophagy both in vitro and in vivo. A compound library containing 27 molecules with a benzotropolone backbone was synthesized and screened for inhibition of recombinant ATG4B. Depending on the benzotropolone compound, inhibition of recombinant ATG4B ranged from 3 to 82%. Active compounds were evaluated in cellular assays to confirm inhibition of ATG4B and suppression of autophagy. Seven compounds inhibited processing of the autophagy protein LC3 and autophagosome formation. Compound UAMC-2526 was selected for further in vivo use because of its fair plasma stability. This compound abolished autophagy both in nutrient-deprived GFP-LC3 mice and in CD1-/- Foxn1nu mice bearing HT29 colorectal tumor xenografts. Moreover, addition of UAMC-2526 to the chemotherapy drug oxaliplatin significantly improved inhibition of tumor growth. Our data indicate that suppression of autophagy via ATG4B inhibition is a feasible strategy to augment existing chemotherapy efficacy and to halt tumor progression.
Volume 138
Pages 150-162
Published 2017-8-15
DOI 10.1016/j.bcp.2017.06.119
PII S0006-2952(17)30442-2
PMID 28642033
MeSH Adenocarcinoma / drug therapy* Adenocarcinoma / pathology Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use* Antineoplastic Combined Chemotherapy Protocols / therapeutic use Autophagy / drug effects* Autophagy-Related Proteins / antagonists & inhibitors* Autophagy-Related Proteins / genetics Autophagy-Related Proteins / metabolism Cell Proliferation / drug effects Colonic Neoplasms / drug therapy* Colonic Neoplasms / pathology Cysteine Endopeptidases / genetics Cysteine Endopeptidases / metabolism Cysteine Proteinase Inhibitors / chemistry Cysteine Proteinase Inhibitors / pharmacology Cysteine Proteinase Inhibitors / therapeutic use* Drug Design* Drug Stability Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism HEK293 Cells HT29 Cells Humans Jurkat Cells Mice, Knockout Mice, Transgenic Microtubule-Associated Proteins / antagonists & inhibitors Microtubule-Associated Proteins / genetics Microtubule-Associated Proteins / metabolism Organoplatinum Compounds / therapeutic use Recombinant Proteins / chemistry Recombinant Proteins / metabolism Tropolone / analogs & derivatives* Tropolone / chemistry Tropolone / pharmacology Tropolone / therapeutic use Xenograft Model Antitumor Assays
IF 4.825
Resource
Mice GFP-LC3#53(RBRC00806)