Hit-to-lead in academia: Discovery of a protein-protein interaction inhibitor of Keap1-Nrf2

Daisuke Yasuda, Rika Obata, Kyoko Takahashi, Tomoyuki Ohe, Tadahiko Mashino

Research output: Contribution to journalReview articlepeer-review


In the process of recent hit-to-lead studies, not only in industry but also in academia, early evaluation of metabolic properties has been one of the key aspects supporting a higher probability of success in drug discovery. In this review, we introduce the development of chemical seeds targeting the Kelch-like ECH-associated protein-1 (Keap1) as an example of an academic hit-to-lead study considering metabolic stability. Keap1 regulates the function of nuclear factor erythroid 2-related factor 2 (Nrf2), which induces various antioxidative or detoxification proteins. An inhibitor of protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 is expected to be a novel target for drug discovery. However, Nrf2 is also activated in several cancers, such as human hepatocellular carcinoma, and causes chemoresistance, which is mediated by phosphorylated p62/Sqstm1 (p-p62), an autophagy-related protein that also undergoes a PPI with Keap1. In this case, an Nrf2 suppressor could be used to attenuate drug resistance.We discovered inhibitors against the Nrf2-Keap1 PPI and p-p62-Keap1 PPI using high-throughput screening and established the synthetic routes for the hit compounds and their derivatives. Furthermore, we assessed the metabolic stability of both of the PPI inhibitors in human liver microsomes and identified the metabolic sites.

Original languageEnglish
Pages (from-to)1059-1065
Number of pages7
JournalYakugaku Zasshi
Issue number8
Publication statusPublished - 2018


  • Drug discovery
  • Metabolic stability
  • P62
  • Protein-protein interaction

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


Dive into the research topics of 'Hit-to-lead in academia: Discovery of a protein-protein interaction inhibitor of Keap1-Nrf2'. Together they form a unique fingerprint.

Cite this