2. Academic Validation
  3. Discovery of sp3-rich diazatricycloundecanes as lysosomotropic autophagy inhibitors

Discovery of sp3-rich diazatricycloundecanes as lysosomotropic autophagy inhibitors

  • Eur J Med Chem. 2024 Oct 5:280:116923. doi: 10.1016/j.ejmech.2024.116923.
Kazuki Miura 1,  Tomoya Doi 2,  Kohei Umedera 2,  Hiroyuki Nakamura 3
Affiliations

Affiliations

  • 1 Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, 226-8501, Japan; School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
  • 2 School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
  • 3 Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, 226-8501, Japan; School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan. Electronic address: hiro@res.titech.ac.jp.
PMID: 39378825 DOI: 10.1016/j.ejmech.2024.116923
Abstract

We have discovered lysosomotropic Autophagy inhibitors from our compound library of sp3-rich diazatricycloundecane skeletons. Compound 1u was identified as the most potent biological activity for LC3-II protein accumulation through the structure-activity relationships (SARs) for LC3-II protein accumulation and anti-proliferative activity at the three freely available substituents (R1-R3) in the diazatricycloundecane skeleton. Compound 1u inhibited lysosome-dependent degradation without affecting autophagosome formation. Furthermore, compound 1u enlarged lysosomes and raised lysosomal pH similar to lysosomotropic agents such as chloroquine, resulting in inhibiting late-stage Autophagy by inducing lysosomal dysfunction. Moreover, compound 1u exhibits excellent drug-like chemical properties, not previously reported for lysosomotropic agents.

Keywords

Autophagy; Lysosomotropic agent; Structure-activity relationship; Three-dimensional skeleton; sp(3)-rich.

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