Synthesis and Structural Optimization of ATG4B Inhibitors for the Attenuation of Autophagy in Glioblastoma

Dalton R. Kim, Meghan J. Orr, Xiaozhou Yu, Hasan H. Munshi, Austin Wang, Claire Trudeau, Ada J. Kwong, Shi Yuan Cheng, Karl A. Scheidt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Glioblastoma, a prevalent malignant CNS tumor, presents a therapeutic challenge because of resistance to standard treatments, including radiation therapy and temozolomide. Both modalities induce autophagy, thereby paradoxically promoting tumor survival. The cysteine protease ATG4B is implicated in this cellular process, which highlights the enzyme as a viable therapeutic target for glioblastoma. We have developed streamlined syntheses for ATG4B inhibitor NSC185058, its derivatives, and fluorogenic ATG4B substrate pim-FG-PABA-AMC. We leveraged these findings to rapidly identify novel compound MJO445, which demonstrates markedly greater potency biochemically and in cells.

Original languageEnglish (US)
Pages (from-to)258-264
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume15
Issue number2
DOIs
StatePublished - Feb 8 2024

Funding

We thank the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS/NIMH; R21NS122375) and Northwestern University for financial support. D.R.K. was supported by the NIH under award numbers F31CA228431 and T32GM008152. M.J.O. was supported by the NIH under award number F30DA050445. H.H.M. thanks Northwestern University for support through a Summer Undergraduate Research Grant and NU Chemistry of Life Processes Institute for an Academic Year Undergraduate Research Grant. A.W. was supported by the NIH under award number T32GM008152. A.J.K. was supported by the NIH under award numbers T32GM105538 and F31CA250353. This work employed the facilities of the High Throughput Analysis Laboratory (HTAL, NU) and the Integrated Molecular Structure Education and Research Center (IMSERC, NU) NMR and MS facilities.

Keywords

  • ATG4
  • Autophagosome
  • Autophagy
  • Cysteine Protease
  • Glioblastoma
  • NSC185058
  • Radiotherapy
  • Temozolomide

ASJC Scopus subject areas

  • Drug Discovery
  • Biochemistry
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Synthesis and Structural Optimization of ATG4B Inhibitors for the Attenuation of Autophagy in Glioblastoma'. Together they form a unique fingerprint.

Cite this