2. Academic Validation
  3. Discovery and Structure-Based Optimization of Novel Atg4B Inhibitors for the Treatment of Castration-Resistant Prostate Cancer

Discovery and Structure-Based Optimization of Novel Atg4B Inhibitors for the Treatment of Castration-Resistant Prostate Cancer

  • J Med Chem. 2022 Mar 24;65(6):4878-4892. doi: 10.1021/acs.jmedchem.1c02113.
Yudai Kudo 1,  Satoshi Endo 1,  Mei Fujita 1,  Atsumi Ota 1,  Yuji O Kamatari 2 3,  Yoshimasa Tanaka 4,  Takeshi Ishikawa 5,  Hayato Ikeda 6,  Takuya Okada 6,  Naoki Toyooka 6,  Naohiro Fujimoto 7,  Toshiyuki Matsunaga 8,  Akira Ikari 1
Affiliations

Affiliations

  • 1 Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
  • 2 Institute for Glyco-core Research (iGCORE), Gifu University, Gifu 501-1193, Japan.
  • 3 United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
  • 4 Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.
  • 5 Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan.
  • 6 Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan.
  • 7 Department of Urology, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
  • 8 Education Center of Green Pharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 502-8585, Japan.
PMID: 35244402 DOI: 10.1021/acs.jmedchem.1c02113
Abstract

Autophagy inhibition is an attractive target for Cancer therapy. In this study, we discovered inhibitors of Atg4B essential for autophagosome formation and evaluated their potential as therapeutics for prostate Cancer. Seventeen compounds were identified as candidates after in silico screening and a thermal shift assay. Among them, compound 17 showed the most potent Atg4B inhibitory activity, inhibited Autophagy induced by anti-castration-resistant prostate Cancer (CRPC) drugs, and significantly enhanced Apoptosis. Although 17 has been known as a Phospholipase A2 (PLA2) inhibitor, other PLA2 inhibitors had no effect on Atg4B and Autophagy. We then performed structural optimization based on molecular modeling and succeeded in developing 21f (by shortening the alkyl chain of 17), which was a potent competitive inhibitor for Atg4B (Ki = 3.1 μM) with declining PLA2 inhibitory potency. Compound 21f enhanced the Anticancer activity of anti-CRPC drugs via Autophagy inhibition. These findings suggest that 21f can be used as an adjuvant drug for therapy with anti-CRPC drugs.

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