Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure

Asahina, Yoshikazu; Wurtz, Nicholas R.; K, Arakawa; Carson, Nancy; Fujii, Kiyoshi; Fukuchi, Kazunori; Garcia, Ricardo Alexandrino; Hsu, Mei-Yin; Ishiyama, Jun‐ichi; Ito, Bruce R.; Kick, Ellen K.; Lupisella, John A.; Matsushima, Shin; Ohata, Kinya; Ostrowski, Jacek; Saito, Yasunori; Tsuda, Kohei; Villarreal, Francisco; Yamada, Hiroki; Yamaoka, Toshikazu; Wexler, Ruth R.; Gordon, David; Kohno, Yasuchi

doi:10.1021/acs.jmedchem.9b02101

Cited by 55 publications

(36 citation statements)

References 29 publications

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“…For example, the dual FPR1/2 agonist compound 17b has been reported to exert anti-inflammatory effects and protect mice from myocardial infarction injury, 59 whereas another compound (Bristol Meyers-Squibb; BMS-986235) has proceeded into a clinical phase I study as a selective FPR2 agonist for prevention of heart failure. 60 Yet another FPR2 selective agonist Act-389949 entered a clinical phase I study but the data obtained show that the surface exposed neutrophil receptors were rapidly lost, although the mechanisms for this were not described. 61 It is clear that better understanding of the basic biology and of the mechanisms that regulate FPRs is highly desirable, and It is generally accepted that activation by receptor specific agonists of chemoattractant GPCRs such as the FPRs, regulates the recruitment of neutrophils from the blood stream to inflammatory sites in infected/damaged tissues and the receptors' downstream signals induce the release/secretion of proteolytic enzymes and ROS.…”

Section: Discussionmentioning

confidence: 99%

“…At present, only a few FPR agonists have progressed to clinical trials. For example, the dual FPR1/2 agonist compound 17b has been reported to exert anti‐inflammatory effects and protect mice from myocardial infarction injury, 59 whereas another compound (Bristol Meyers‐Squibb; BMS‐986235) has proceeded into a clinical phase I study as a selective FPR2 agonist for prevention of heart failure 60 . Yet another FPR2 selective agonist Act‐389949 entered a clinical phase I study but the data obtained show that the surface exposed neutrophil receptors were rapidly lost, although the mechanisms for this were not described 61 .…”

Section: Discussionmentioning

confidence: 99%

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Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2 complex

Lind

Dahlgren

Holmdahl

et al. 2020

Journal of Leukocyte Biology

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The formyl peptide receptors FPR1 and FPR2 are abundantly expressed by neutrophils, in which they regulate proinflammatory tissue recruitment of inflammatory cells, the production of reactive oxygen species (ROS), and resolution of inflammatory reactions. The unique dual functionality of the FPRs makes them attractive targets to develop FPR-based therapeutics as novel anti-inflammatory treatments. The small compound RE-04-001 has earlier been identified as an inducer of ROS in differentiated HL60 cells but the precise target and the mechanism of action of the compound was has until now not been elucidated. In this study, we reveal that RE-04-001 specifically targets and activates FPR1, and the concentrations needed to activate the neutrophil NADPH-oxidase was very low (EC 50 ∼1 nM). RE-04-001 was also found to be a neutrophil chemoattractant, but when compared to the prototype FPR1 agonist N-formyl-Met-Leu-Phe (fMLF), the concentrations required were comparably high, suggesting that signaling downstream of the RE-04-001-activated-FPR1 is functionally selective. In addition, the RE-04-001-induced response was strongly biased toward the PLC-PIP 2-Ca 2+ pathway and ERK1/2 activation but away from-arrestin recruitment. Compared to the peptide agonist fMLF, RE-04-001 is more resistant to inactivation by the MPO-H 2 O 2-halide system. In summary, this study describes RE-04-001 as a novel small molecule agonist specific for FPR1, which displays a biased signaling profile that leads to a functional selective activating of human neutrophils. RE-04-001 is, therefore, a useful tool, not only for further mechanistic studies of the regulatory role of FPR1 in inflammation in vitro and in vivo, but also for developing FPR1-specific drug therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2 complex

Lind

Dahlgren

Holmdahl

et al. 2020

Journal of Leukocyte Biology

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“…An unsaturated hydrocarbon containing three double bonds between carbon atoms. of experimental heart failure 158 . Beyond lipoxins, great interest exists in the generation of synthetic resolvins.…”

Section: Triene Corementioning

confidence: 99%

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function

et al. 2021

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“…While FPRs are usually triggered by microbial derived formylated peptides, endogenous proteins or lipopeptides, small compounds and peptides acting as exogenous FPR agonists have been identified. Examples are the FPR1 agonist RE-04-001, FPR2 agonists BMS-986235 and Act-389949, and dual FPR1/2 agonists such as compound 17b (252)(253)(254)(255).…”

Section: Stimulation Of Endogenous Ros Sourcesmentioning

confidence: 99%

Raising the ‘Good’ Oxidants for Immune Protection

Dumas

Knaus

2021

Front. Immunol.

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Redox medicine is a new therapeutic concept targeting reactive oxygen species (ROS) and secondary reaction products for health benefit. The concomitant function of ROS as intracellular second messengers and extracellular mediators governing physiological redox signaling, and as damaging radicals instigating or perpetuating various pathophysiological conditions will require selective strategies for therapeutic intervention. In addition, the reactivity and quantity of the oxidant species generated, its source and cellular location in a defined disease context need to be considered to achieve the desired outcome. In inflammatory diseases associated with oxidative damage and tissue injury, ROS source specific inhibitors may provide more benefit than generalized removal of ROS. Contemporary approaches in immunity will also include the preservation or even elevation of certain oxygen metabolites to restore or improve ROS driven physiological functions including more effective redox signaling and cell-microenvironment communication, and to induce mucosal barrier integrity, eubiosis and repair processes. Increasing oxidants by host-directed immunomodulation or by exogenous supplementation seems especially promising for improving host defense. Here, we summarize examples of beneficial ROS in immune homeostasis, infection, and acute inflammatory disease, and address emerging therapeutic strategies for ROS augmentation to induce and strengthen protective host immunity.

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Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure

Cited by 55 publications

References 29 publications

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2 complex

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2 complex

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function

Raising the ‘Good’ Oxidants for Immune Protection

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