Discovery of 1,4-Benzodiazepine-2,5-dione (BZD) Derivatives as Dual Nucleotide Binding Oligomerization Domain Containing 1/2 (NOD1/NOD2) Antagonists Sensitizing Paclitaxel (PTX) To Suppress Lewis Lung Carcinoma (LLC) Growth in Vivo

Nucleotide-binding oligomerization
domain-like receptors (NLRs) are intracellular sensors of pathogen-associated
molecular patterns (PAMPs) and damage-associated molecular
patterns (DAMPs). Previously, we reported nucleotide-binding oligomerization
domain-containing protein 1 (NOD1) antagonists (11, 12) and a NOD2 antagonist (9) that sensitized
docetaxel (DTX) or paclitaxel (PTX) treatment for breast or lung cancer.
In this article, we describe for the first time a 1,4-benzodiazepine-2,5-dione
(BZD) derivative (26bh) that acts as a dual NOD1/NOD2
antagonist and inhibits both nuclear factor κB (NF-κB)
and mitogen-activated protein kinase (MAPK) inflammatory signaling,
thereby sensitizing PTX to suppress Lewis lung carcinoma (LLC) growth.
After investigation of the compound’s cytotoxicity, a systematic
structure–activity relationship (SAR) was completed and revealed
several key factors that were necessary to maintain antagonistic ability.
This study establishes the possibility for using adjuvant treatment
to combat cancer by antagonizing both NOD1 and NOD2 signaling.