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A Novel C-C Chemoattractant Cytokine (Chemokine) Receptor 6 (CCR6) Antagonist (PF-07054894) Distinguishes between Homologous Chemokine Receptors, Increases Basal Circulating CCR6+ T Cells, and Ameliorates Interleukin-23-Induced Skin Inflammation.
Li, Wei; Crouse, Kimberly K; Alley, Jennifer; Frisbie, Richard K; Fish, Susan C; Andreyeva, Tatyana A; Reed, Lori A; Thorn, Mitchell; DiMaggio, Giovanni; Donovan, Carol B; Bennett, Donald; Garren, Jeonifer; Oziolor, Elias; Qian, Jesse; Newman, Leah; Vargas, Amanda P; Kumpf, Steven W; Steyn, Stefan J; Schnute, Mark E; Thorarensen, Atli; Hegen, Martin; Stevens, Erin; Collinge, Mark; Lanz, Thomas A; Vincent, Fabien; Vincent, Michael S; Berstein, Gabriel.
Afiliação
  • Li W; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Crouse KK; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Alley J; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Frisbie RK; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Fish SC; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Andreyeva TA; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Reed LA; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Thorn M; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • DiMaggio G; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Donovan CB; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Bennett D; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Garren J; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Oziolor E; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Qian J; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Newman L; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Vargas AP; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Kumpf SW; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Steyn SJ; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Schnute ME; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Thorarensen A; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Hegen M; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Stevens E; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Collinge M; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Lanz TA; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Vincent F; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Vincent MS; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
  • Berstein G; Inflammation and Immunology Research Unit (W.L., K.K.C., J.A., S.C.F., T.A.A., M.H., M.S.V., G.B.), Biostatistics (D.B., J.G.), and Medicine Design (S.J.S., M.E.S., A.T.), Pfizer, Inc., Cambridge, Massachusetts, and Primary Pharmacology Group (R.K.F., F.V.), Clinical Biomarkers (M.T., E.S.), and Dru
J Pharmacol Exp Ther ; 386(1): 80-92, 2023 07.
Article em En | MEDLINE | ID: mdl-37142443
ABSTRACT
Blocking chemokine receptor C-C chemoattractant cytokine (chemokine) receptor (CCR) 6-dependent T cell migration has therapeutic promise in inflammatory diseases. PF-07054894 is a novel CCR6 antagonist that blocked only CCR6, CCR7, and C-X-C chemoattractant cytokine (chemokine) receptor (CXCR) 2 in a ß-arrestin assay panel of 168 G protein-coupled receptors. Inhibition of CCR6-mediated human T cell chemotaxis by (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (PF-07054894) was insurmountable by CCR6 ligand, C-C motif ligand (CCL) 20. In contrast, blockade of CCR7-dependent chemotaxis in human T cells and CXCR2-dependent chemotaxis in human neutrophils by PF-07054894 were surmountable by CCL19 and C-X-C motif ligand 1, respectively. [3H]-PF-07054894 showed a slower dissociation rate for CCR6 than for CCR7 and CXCR2 suggesting that differences in chemotaxis patterns of inhibition could be attributable to offset kinetics. Consistent with this notion, an analog of PF-07054894 with fast dissociation rate showed surmountable inhibition of CCL20/CCR6 chemotaxis. Furthermore, pre-equilibration of T cells with PF-07054894 increased its inhibitory potency in CCL20/CCR6 chemotaxis by 10-fold. The functional selectivity of PF-07054894 for inhibition of CCR6 relative to CCR7 and CXCR2 is estimated to be at least 50- and 150-fold, respectively. When administered orally to naïve cynomolgus monkeys, PF-07054894 increased the frequency of CCR6+ peripheral blood T cells, suggesting that blockade of CCR6 inhibited homeostatic migration of T cells from blood to tissues. PF-07054894 inhibited interleukin-23-induced mouse skin ear swelling to a similar extent as genetic ablation of CCR6. PF-07054894 caused an increase in cell surface CCR6 in mouse and monkey B cells, which was recapitulated in mouse splenocytes in vitro. In conclusion, PF-07054894 is a potent and functionally selective CCR6 antagonist that blocks CCR6-mediated chemotaxis in vitro and in vivo. SIGNIFICANCE STATEMENT The chemokine receptor, C-C chemoattractant cytokine (chemokine) receptor 6 (CCR6) plays a key role in the migration of pathogenic lymphocytes and dendritic cells into sites of inflammation. (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (PF-07054894) is a novel CCR6 small molecule antagonist that illustrates the importance of binding kinetics in achieving pharmacological potency and selectivity. Orally administered PF-07054894 blocks homeostatic and pathogenic functions of CCR6, suggesting that it is a promising therapeutic agent for the treatment of a variety of autoimmune and inflammatory diseases.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quimiocinas CC / Interleucina-23 Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Quimiocinas CC / Interleucina-23 Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article