Synthesis And Evaluation Of Fpr1 Inhibitors As A Novel Treatment For Cancers.

Abstract The formyl peptide receptor-1 (FPR1) is a member of 7TM GPCRs. It was first identified in phagocytic leukocytes and has been found to play a role in innate immune response to bacterial infection. Recently FPR1 has been shown to be overexpressed in many malignant cancers and particularly in glioblastoma. Our more recent investigation has shown that increased expression of FPR1 in cancer is most notably prominent in the periphery of the necrotic foci. We have hypothesised that FPR1 activation by molecules released from the hypoxic/necrotic core of tumours (including Annexin-A1 and short chain-N-formylated peptides such as fMLF) leads to increased proliferation, invasion, resistance, and angiogenesis. Therefore, antagonism of FPR1 should prevent these key drivers of malignancy in cancer. Here we present the synthesis and biological evaluation of a series of pyrazole compounds that potently inhibit FPR1. In addition, we provide a computational rationale for their relative potency based on docking of the molecules inside a homology model of FPR1. We will also show the efficacy of our lead compound, ICT12035 (IC50 =30nM in calcium mobilisation assay) in a number 2D and 3D proliferation and invasion assays in vitro, and in an in vivo animal model where it arrests tumour growth. Furthermore, we demonstrate the significance of FPR1 in tumour resistance by showing that ICT12035 increases the efficacy of cytotoxic agents TMZ and BCNU, as well as radiation in vitro. ICT12035 significantly abrogates the effects fMLF induced resistance to TMZ and BCNU in in U87 cell lines. A similar effect is also observed in a cell viability assay where in the addition of ICT12035 significantly increased cell death following radiation. Our findings suggest that inhibiting FPR1 in combination with chemotherapy and radiotherapy could be a new treatment strategy against cancers. Citation Format: Amin Aghamohammadi, Di Lu, Anwar Salem, Patricia A. Cooper, Steven D. Shnyder, Victoria Vinader, Kamyar Afarinkia. Synthesis and evaluation of FPR1 inhibitors as a novel treatment for cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1331.