2. Academic Validation
  3. Discovery of novel integrase-LEDGF/p75 allosteric inhibitors based on a benzene scaffold

Discovery of novel integrase-LEDGF/p75 allosteric inhibitors based on a benzene scaffold

  • Bioorg Med Chem. 2020 Sep 1;28(17):115643. doi: 10.1016/j.bmc.2020.115643.
Shuichi Sugiyama 1,  Tsutomu Iwaki 2,  Yoshinori Tamura 2,  Kenji Tomita 2,  Eriko Matsuoka 2,  Shuhei Arita 2,  Takahiro Seki 2,  Tomokazu Yoshinaga 2,  Takashi Kawasuji 2
Affiliations

Affiliations

  • 1 Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: [email protected].
  • 2 Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited, 1-1, Futabacho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
PMID: 32773094 DOI: 10.1016/j.bmc.2020.115643
Abstract

We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the Antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent Antiviral activity (EC50 (NL432) = 3.9 nM) than BI-224436 (EC50 (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.

Keywords

HIV; INLAIs (integrase-LEDGF/p75 allosteric inhibitors); LEDGF (lens epithelium-derived growth factor).

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