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

Abstract

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.

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

“…The role of NOD2 in cancer immunity is controversially reported 12,45,46 , and it varies depending on the types of cancer. NOD2 is an important component of the innate immune system and it constitutes an interesting regulatory target in terms of strengthening the immune response against cancer cells.…”

“…Therefore several types of NOD2 agonists were synthesized which exhibited favorable anticancer activity 12 . However, another study showed that NOD2 antagonist inhibited both NF-κB and MAPK inflammatory signaling, and played an adjuvant role to paclitaxel (PTX) to suppress Lewis lung carcinoma (LLC) growth 45 . In addition, it has been reported that MDP analogs can inhibit the recruitment of myeloid-derived suppressor cells (MDSCs) to exert their anti-tumor effect 47 .…”

Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications

“…Therefore, NOD receptors appear to be potentially important targets of therapeutic intervention in sepsis and septic shock. Presently, antagonists of NOD1 and NOD2 are being developed . Most of these compounds are derivatives of heterocyclic bicyclic compounds such as indole, purine, or benzimidazole .…”

“…Presently, antagonists of NOD1 and NOD2 are being developed . Most of these compounds are derivatives of heterocyclic bicyclic compounds such as indole, purine, or benzimidazole . Some of them are dual NOD1/NOD2 antagonists, whereas others are selective towards NOD1 or NOD2 .…”

“…[99][100][101][102] Most of these compounds are derivatives of heterocyclic bicyclic compounds such as indole, purine, or benzimidazole. [99][100][101][102] Some of them are dual NOD1/NOD2 antagonists, 99,102 whereas others are selective towards NOD1 100 or NOD2. 101 Therapeutic efficacy of these drugs alone or in combination with anti-LPS agents should be tested in preclinical models of sepsis and septic shock.…”