Lysophospholipid receptors in drug discovery

Abstract

Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1-phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell-surface G protein-coupled receptors, LPA1-6, S1P1-5, LPI1, and LysoPS1-3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems. Advances in the LP receptor field have enabled the development of novel small molecules targeting LP receptors for several diseases. Most notably, fingolimod (FTY720, Gilenya, Novartis), an S1P receptor modulator, became the first FDA-approved medicine as an orally bioavailable drug for treating relapsing forms of multiple sclerosis. This success is currently being followed by multiple, mechanistically related compounds targeting S1P receptor subtypes, which are in various stages of clinical development. In addition, an LPA1 antagonist, BMS-986020 (Bristol-Myers Squibb), is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis, as a distinct compound, SAR100842 (Sanofi) for the treatment of systemic sclerosis and related fibrotic diseases. This review summarizes the current state of drug discovery in the LP receptor field.

Keywords: Cannabinoids; FTY720; Fingolimod; GPCR; Idiopathic pulmonary fibrosis; LPA; LPS; Multiple sclerosis; S1P.

Figure 1. Chronology of the LP field, LP and other lipid receptors, and overview of proximal LP signaling features

(A) Chronology of the LP receptor field. Vertical bars indicate the number of publications within 5-year bins, which were searched in PubMed with unabbreviated names of the indicated keywords. (B) Chronological table for identification of lipid GPCRs. LP receptors are noted in red. (C) The chemical structures of LPs, GPCR names, and associated heterotrimeric G-proteins as defined by their Gα subunits.

Figure 2. Disease mechanisms being accessed by LP-based drug discovery and compounds in clinical development

(A) LP receptor-based compounds currently in clinical trials. NLM, National Laboratory of Medicine; IPF, idiopathic pulmonary fibrosis; CIDP, chronic inflammatory demyelinating polyneuropathy. (B) Multiple sclerosis pathology and actions of FTY720. Lymphocytes expressing S1P₁ migrate from lymph nodes to blood based on S1P concentration differences. FTY720 redistributes these lymphocytes into lymph nodes (i.e., secondary lymphoid organs), resulting in reduced entry of pathogenic lymphocytes into the CNS. FTY720 also inhibits astrocyte function, may alter oligodendrocyte function via S1P₅ and results in reduced inflammation, demyelination, with possibly other beneficial functions. As, astrocytes; BBB, blood brain barrier; CNS, central nervous system; Neu, neuron; OL, oligodendrocyte. (C) IPF pathology and accessed mechanisms for an LPA₁ antagonist. Circulating and resident fibroblasts (Fb) are recruited to the injured site, which may be interrupted by LPA₁ antagonists. Epithelial cells differentiate into fibroblasts by epithelial mesenchymal transition (EMT). These fibroblasts differentiate into myofibroblasts (MyoFb), which accelerate fibrosis and may also be inhibited by LPA₁ antagonists.