Design, synthesis, evaluation, and structural studies of C2-Symmetric Small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 protein-protein interaction

Subhadwip Basu, Jeffrey Yang, Bin Xu, Katarzyna Magiera-Mularz, Lukasz Skalniak, Bogdan Musielak, Vladyslav Kholodovych, Tad A. Holak, Longqin Hu

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

A series of C2-symmetric inhibitors was designed and evaluated for inhibitory activity against the programmed cell death-1/programmed death-ligand 1(PD-1/PD-L1) protein-protein interaction (PPI) in a homogenous time-resolved fluorescence (HTRF) assay and PD-1 signaling in cell-based coculture assays. C2-symmetric inhibitors 2a (LH1306) and 2b (LH1307) exhibited IC50 values of 25 and 3.0 nM, respectively, in the HTRF assay. While 2a was ∼3.8-fold more potent than previously reported inhibitor 1a, 2b could not be differentiated from 1b due to their high potency and the limit of our HTRF assay conditions. In one cell-based coculture PD-1 signaling assay, 2a and 2b were 8.2- and 2.8-fold more potent in inhibiting PD-1 signaling than 1a and 1b, respectively. NMR and X-ray cocrystal structural studies provided more structural insights into the interaction between 2b and PD-L1; 2b binds to PD-L1 at the PD-1 binding site and induces the formation of a more symmetrically arranged PD-L1 homodimer than that previously reported for other inhibitors.

Original languageEnglish (US)
Pages (from-to)7250-7263
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number15
DOIs
StatePublished - Aug 8 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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