Intrinsic signaling pathways modulate targeted protein degradation

  • Nat Commun. 2024 Jul 2;15(1):5379. doi: 10.1038/s41467-024-49519-z.
Yuki Mori  #  1  2 ,  Yoshino Akizuki  #  1  2 ,  Rikuto Honda  1  2 ,  Miyu Takao  2 ,  Ayaka Tsuchimoto  1  2 ,  Sota Hashimoto  3 ,  Hiroaki Iio  3 ,  Masakazu Kato  3  4 ,  Ai Kaiho-Soma  1 ,  Yasushi Saeki  5  6 ,  Jun Hamazaki  3 ,  Shigeo Murata  3 ,  Toshikazu Ushijima  7 ,  Naoko Hattori  7 ,  Fumiaki Ohtake  8  9
Affiliations
  • 1. Laboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
  • 2. Graduate School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
  • 3. Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
  • 4. Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Nakano-ku, Tokyo, 1648530, Japan.
  • 5. Division of Protein Metabolism, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
  • 6. Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Sciences, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
  • 7. Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
  • 8. Laboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. [email protected].
  • 9. Graduate School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. [email protected].
  • # Contributed equally.
PMID: 38956052 DOI: 10.1038/s41467-024-49519-z
Abstract

Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the Anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2VHL- or CRL4CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK Inhibitor GSK2606414), and protein stabilization (HSP90 Inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4-PROTAC-CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced Apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.

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