Nonpeptidic quinazolinone derivatives as dual nucleotide-binding oligomerization domain-like receptor 1/2 antagonists for adjuvant cancer chemotherapy

Highlights

• A new class of quinazolinone derivatives as dual NOD1/2 antagonists was synthesized.

• 36b exhibited potent inhibitory activity against NOD1/2 with a long T_1/2 in vitro.

• 36b sensitized PTX treatment in B16-tumor bearing mice.

Abstract

Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD1/2) receptors are potential immune checkpoints. In this article, a quinazolinone derivative (36b) as a NOD1/2 dual antagonist was identified that significantly sensitizes B16 tumor-bearing mice to paclitaxel treatment by inhibiting both nuclear factor κB (NF-κB) and mitogen-activated protein kinase inflammatory signaling that mediated by NOD1/2.

Introduction

Currently, immunotherapy primarily aims to artificially stimulate the immune system to improve its natural ability to stop or eliminate cancer [1]. Therefore, the identification and evaluation of novel immune targets has become an important goal of research. Because the cytosolic nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD1 and NOD2) receptors are important components of the innate immune system, they have been pharmacologically targeted to enhance the immune response against cancer cells [[2], [3], [4], [5], [6], [7]]. Many NOD1/2 agonists have been discovered: Mifamurtide, for example, has already been approved for treating high-grade, nonmetastatic, resectable osteosarcoma after surgical excision in children to young adults [8]. However, a shift has occurred in recent with the emerging knowledge that NOD antagonists facilitate the chemotherapy of some cancers [9]. For instance, Zitvogel and coworkers have identified the NOD2 receptor as a ‘gut immune checkpoint’ based on the evidence that NOD2 curtails cyclophosphamide (CTX)-induced cancer immunosurveillance by limiting the relocation of microbes [10]. Ferri’s group demonstrated the NOD1 receptor as a putative therapeutic target in inflammation-mediated colon cancer metastasis. The experimental results revealed that NOD1 activation increased colorectal cancer cell adhesion, migration and metastasis via the p38 mitogen activated protein kinase pathway [11].

In 2011, we first reported a conjugate of paclitaxel (MTC-220, 1) and a muramyl dipeptide (MDP) derivative that was superior to PTX alone for treatment of Lewis lung carcinoma (LLC) in mice. MDP is the natural ligand for NOD2, however, we found that the prototype for MTC-220 (compound 2) is responsible for remodeling the tumor microenvironment (TME) by inhibiting NOD2 signaling and limiting PTX-induced cancer immunosurveillance in mice [12,13]. In addition, conjugates (3 and 4) of docetaxel (DTX) and MDP derivatives were designed as another chemical class of NOD1 antagonists for breast cancer treatment [14]. Effective antagonists for cancer adjuvant treatment should therefore antagonize both NOD1 and NOD2 signaling. Pharmacologically targeting both the NOD1 and NOD2 signaling pathways is expected to have a broad therapeutic utility for cancer treatment. Small molecules quinazolinones (5) and 2-aminobenzimidazoles (6) were discovered and identified as NOD1 antagonists in 2011 and 2014, respectively [[15], [16], [17]]. The NOD2 selective antagonist (7) is an imidazole derivative that was disclosed via high-throughput screening [18]. Jakopin’s group reported in 2016 a dual NOD1/2 antagonist (Fig. 1, 8) based on an indole scaffold [19,20]. Compound 9 was the first dual NOD1/2 antagonist based on a 1,4-benzodiazepine-2,5-dione derivative which sensitized chemotherapy with PTX to LLC in animals [21]. In this article, we perform the synthesis and evaluation of quinazolinone derivatives aiming to identify novel NOD1/2 dual antagonists. We have demonstrated compound 36b as a novel NOD1/2 dual antagonist that can significantly sensitize B16 tumor-bearing mice to PTX treatment.