Kevin R. Lynch

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Primary Appointment

Professor and Vice Chair, Pharmacology

Education

  • BS, Microbiology, Pennsylvania State University, University Park, PA
  • MS, Microbiology, University of Rhode Island, Kingston, RI
  • PhD, Molecular Biology, University of Rhode Island, Kingston, RI
  • Postdoc, Molecular Biology, Columbia University

Research Disciplines

Biochemistry, Biotechnology, Cardiovascular Biology, Molecular Pharmacology, Translational Science

Research Interests

Chemical biology of sphingosine 1-phosphate

Research Description

The over-arching goal of our research is to understand better the biology of sphingosine 1-phosphate (S1P), particularly in the context of disease. S1P is a pleiotropic extracellular lipid that is implicated in control of lymphocyte trafficking, heart rate and vascular leakage. Recently, a S1P receptor agonist pro-drug, fingolimod, was approved as immune system modulator in the treatment of multiple sclerosis.
Our central strategy remains the development of tools (mostly small molecules) with which to probe S1P biology. We complement our chemical biology approach with mouse genetics. The new chemical entities that we have developed including S1P receptor agonists and antagonists. The synthesis of these molecules was accomplished in the laboratory of our long term collaborator, Professor Timothy L. Macdonald (Univ. VA Chemistry).
The current focus of our work is to develop reagents to explore the mechanisms whereby S1P plasma levels (300 nM) are maintained and consequences of manipulating vascular S1P tone. To this end, we have developed potent inhibitors of the S1P synthetic enzyme, sphingosine kinase (SphK). Administration of our inhibitors to mice and rats revealed that circulating S1P decreased rapidly (minutes) in response to SphK1 inhibition. We have also developed SphK2-selective inhibitors in collaboration with Professor Webster L. Santos (VA Tech Chemistry). Among our current challenges is modifying our SphK inhibitors to make them more persistent in vivo while retaining potency and selectivity. Such molecules will allow testing of the hypothesis that interdicting S1P synthesis at the level of SphK will influence the course of disease in models of inflammation and cancer.
Our work is funded by the National Institutes of Health (NIGMS, NICHD), a private foundation and the pharmaceutical industry.

Personal Statement

The over-arching goal of this laboratorys research is to understand better
the biology of lysophospholipid signaling, particularly in the context of pathologies.
The central strategy remains the development of tools (mostly small molecules)
with which to probe lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P)
biology. We complement this chemical biology approach with mouse genetics. The
new chemical entities developed recently include a LPA3 receptor antagonist, a
LPA1/LPA3 receptor selective antagonist and inhibitors of the LPA-producing phospholipase,
autotaxin. Further, we have identified S1P receptor agonists (including pro-drugs)
and a S1P1/S1P3 receptor antagonist. The syntheses of these molecules were done
in the laboratory of our long term collaborator, Professor Timothy L. Macdonald
(UVA Department of Chemistry).
Using the latest generation of compounds, we found that LPA receptor antagonists
are anti-angiogenic in the chicken chorioallantoic membrane (CAM) assay. These
antagonists are being taken forward to angiogenesis assays in rodents. The Macdonald
Lab provided us recently with a high affinity LPA1 receptor antagonist that is
stable metabolically. In addition to the aforementioned angiogenesis assays, this
compound is being tested currently in several neoplasia models including melanoma,
ovarian and breast cancer. We are using an invertebrate (brown recluse spider)
lysophospholipase D to learn the effects of local LPA generation on angiogenesis
and tumor development in mice. The LPA receptor types implicated in biologic processes
by our small molecules are being tested also using LPA1 and LPA3 receptor knock-out
mice.
Among our S1P receptor compounds, we are concentrating on S1P receptor agonist
pro-drugs and S1P1 receptor antagonists. S1P1 receptor agonists block lymphocyte
egress from lymph nodes and thereby modulate the immune system. The lead drug
in this class, FTY720 (fingolimod), is efficacious in autoimmune disease models.
We used structure activity relationships of our set of sphingosine analogs and
our sphingosine kinase 2 (SPHK2) null mice to document recently that our S1P prodrugs,
like FTY720, are activated by SPHK2 catalyzed phosphorylation. We are particularly
interested in using our S1P agonist compounds to interdict the development of
type 1 diabetes and treat its complications such as atherosclerosis and neuropathic
pain. We are taking our lead S1P1 receptor antagonist forward into cancer and
angiogenesis models.

Training

  • Biotechnology Training Grant
  • Training in Cell and Molecular Biology
  • Training in the Pharmacological Sciences

Selected Publications

Cao R, Li J, Kharel Y, Zhang C, Morris E, Santos WL, Lynch KR, Zuo Z, Hu S, Photoacoustic microscopy reveals the hemodynamic basis of sphingosine 1-phosphate-induced neuroprotection against ischemic stroke., 2019; Theranostics. 8(22) 6111-6120. PMID: 30613286 | PMCID: PMC6299683

Mehaffey JH, Charles EJ, Narahari AK, Schubert S, Laubach VE, Teman NR, Lynch KR, Kron IL, Sharma AK, Increasing circulating sphingosine-1-phosphate attenuates lung injury during ex vivo lung perfusion., 2018; The Journal of thoracic and cardiovascular surgery. 156(2) 910-917. PMID: 29609890 | PMCID: PMC6056006

Kharel Y, Agah S, Huang T, Mendelson AJ, Eletu OT, Barkey-Bircann P, Gesualdi J, Smith JS, Santos WL, Lynch KR, Saccharomyces cerevisiae as a platform for assessing sphingolipid lipid kinase inhibitors., 2018; PloS one. 13(4) e0192179. PMID: 29672528 | PMCID: PMC5908134

Adamiak M, Chelvarajan L, Lynch KR, Santos WL, Abdel-Latif A, Ratajczak MZ, Correction: Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells., 2018; Oncotarget. 9(75) 34189. PMID: 30344931 | PMCID: PMC6183342

Childress ES, Kharel Y, Brown AM, Bevan DR, Lynch KR, Santos WL, Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity., 2017; Journal of medicinal chemistry. 60(9) 3933-3957. PMID: 28406646 | PMCID: PMC6047346

Adamiak M, Chelvarajan L, Lynch KR, Santos WL, Abdel-Latif A, Ratajczak MZ, Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells., 2017; Oncotarget. 8(39) 65588-65600. PMID: 29029455 | PMCID: PMC5630355

Congdon MD, Kharel Y, Brown AM, Lewis SN, Bevan DR, Lynch KR, Santos WL, Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene-Based Sphingosine Kinase 2 Inhibitors., 2016; ACS medicinal chemistry letters. 7(3) 229-34. PMID: 26985306 | PMCID: PMC4789682

Houck JD, Dawson TK, Kennedy AJ, Kharel Y, Naimon ND, Field SD, Lynch KR, Macdonald TL, Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles., 2016; ACS medicinal chemistry letters. 7(5) 487-92. PMID: 27190598 | PMCID: PMC4867490

Lynch KR, Thorpe SB, Santos WL, Sphingosine kinase inhibitors: a review of patent literature (2006-2015)., 2016; Expert opinion on therapeutic patents. 26(12) 1409-1416. PMID: 27539678 | PMCID: PMC5773104

Bajwa A, Huang L, Kurmaeva E, Ye H, Dondeti KR, Chroscicki P, Foley LS, Balogun ZA, Alexander KJ, Park H, Lynch KR, Rosin DL, Okusa MD, Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-γ., 2016; Journal of the American Society of Nephrology : JASN. 28(4) 1145-1161. PMID: 27799486 | PMCID: PMC5373443

Perry HM, Huang L, Ye H, Liu C, Sung SJ, Lynch KR, Rosin DL, Bajwa A, Okusa MD, Endothelial Sphingosine 1âPhosphate Receptorâ1 Mediates Protection and Recovery from Acute Kidney Injury., 2016; Journal of the American Society of Nephrology : JASN. 27(11) 3383-3393. PMID: 26961351 | PMCID: PMC5084889

Stone ML, Sharma AK, Zhao Y, Charles EJ, Huerter ME, Johnston WF, Kron IL, Lynch KR, Laubach VE, Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury., 2015; American journal of physiology. Lung cellular and molecular physiology. 308(12) L1245-52. PMID: 25910934 | PMCID: PMC4587601

Kharel Y, Morris EA, Congdon MD, Thorpe SB, Tomsig JL, Santos WL, Lynch KR, Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels., 2015; The Journal of pharmacology and experimental therapeutics. 355(1) 23-31. PMID: 26243740 | PMCID: PMC4576667

Nakayama J, Raines TA, Lynch KR, Slack-Davis JK, Decreased peritoneal ovarian cancer growth in mice lacking expression of lipid phosphate phosphohydrolase 1., 2015; PloS one. 10(3) e0120071. PMID: 25769037 | PMCID: PMC4359083

Congdon MD, Childress ES, Patwardhan NN, Gumkowski J, Morris EA, Kharel Y, Lynch KR, Santos WL, Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors., 2015; Bioorganic & medicinal chemistry letters. 25(21) 4956-4960. PMID: 25862200 | PMCID: PMC4580500

Patwardhan NN, Morris EA, Kharel Y, Raje MR, Gao M, Tomsig JL, Lynch KR, Santos WL, Structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors: discovery of SphK1- and SphK2-selective inhibitors., 2015; Journal of medicinal chemistry. 58(4) 1879-1899. PMID: 25643074 | PMCID: PMC4557804

Taddeo EP, Laker RC, Breen DS, Akhtar YN, Kenwood BM, Liao JA, Zhang M, Fazakerley DJ, Tomsig JL, Harris TE, Keller SR, Chow JD, Lynch KR, Chokki M, Molkentin JD, Turner N, James DE, Yan Z, Hoehn KL, Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle., 2014; Molecular metabolism. 3(2) 124-34. PMID: 24634818 | PMCID: PMC3953683

Awojoodu AO, Keegan PM, Lane AR, Zhang Y, Lynch KR, Platt MO, Botchwey EA, Acid sphingomyelinase is activated in sickle cell erythrocytes and contributes to inflammatory microparticle generation in SCD., 2014; Blood. 124(12) 1941-50. PMID: 25075126 | PMCID: PMC4168349

Santos WL, Lynch KR, Drugging sphingosine kinases., 2014; ACS chemical biology. 10(1) 225-33. PMID: 25384187 | PMCID: PMC4301069

Kenwood BM, Weaver JL, Bajwa A, Poon IK, Byrne FL, Murrow BA, Calderone JA, Huang L, Divakaruni AS, Tomsig JL, Okabe K, Lo RH, Cameron Coleman G, Columbus L, Yan Z, Saucerman JJ, Smith JS, Holmes JW, Lynch KR, Ravichandran KS, Uchiyama S, Santos WL, Rogers GW, Okusa MD, Bayliss DA, Hoehn KL, Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane., 2014; Molecular metabolism. 3(2) 114-23. PMID: 24634817 | PMCID: PMC3953706

Bajwa A, Rosin DL, Chroscicki P, Lee S, Dondeti K, Ye H, Kinsey GR, Stevens BK, Jobin K, Kenwood BM, Hoehn KL, Lynch KR, Okusa MD, Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury., 2014; Journal of the American Society of Nephrology : JASN. () . PMID: 25145931

Awojoodu AO, Ogle ME, Sefcik LS, Bowers DT, Martin K, Brayman KL, Lynch KR, Peirce-Cottler SM, Botchwey E, Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis., 2013; Proceedings of the National Academy of Sciences of the United States of America. 110(34) 13785-90. PMID: 23918395 | PMCID: PMC3752259

Bajwa A, Huang L, Ye H, Dondeti K, Song S, Rosin DL, Lynch KR, Lobo PI, Li L, Okusa MD, Dendritic cell sphingosine 1-phosphate receptor-3 regulates Th1-Th2 polarity in kidney ischemia-reperfusion injury., 2012; Journal of immunology (Baltimore, Md. : 1950). 189(5) 2584-96. PMID: 22855711 | PMCID: PMC3433235

Knott K, Kharel Y, Raje MR, Lynch KR, Santos WL, Effect of alkyl chain length on sphingosine kinase 2 selectivity., 2012; Bioorganic & medicinal chemistry letters. 22(22) 6817-20. PMID: 22321213 | PMCID: PMC3394931

Lynch KR, Building a better sphingosine kinase-1 inhibitor., 2012; The Biochemical journal. 444(1) e1-2. PMID: 22533672

Gellett AM, Kharel Y, Sunkara M, Morris AJ, Lynch KR, Biosynthesis of alkyl lysophosphatidic acid by diacylglycerol kinases., 2012; Biochemical and biophysical research communications. 422(4) 758-63. PMID: 22627129 | PMCID: PMC3377814

Kharel Y, Raje M, Gao M, Gellett AM, Tomsig JL, Lynch KR, Santos WL, Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate., 2012; The Biochemical journal. 447(1) 149-57. PMID: 22747486 | PMCID: PMC3443596

Kharel Y, Mathews TP, Kennedy AJ, Houck JD, Macdonald TL, Lynch KR, A rapid assay for assessment of sphingosine kinase inhibitors and substrates., 2011; Analytical biochemistry. 411(2) 230-5. PMID: 21216217 | PMCID: PMC3049835

Awad AS, Rouse MD, Khutsishvili K, Huang L, Bolton WK, Lynch KR, Okusa MD, Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes., 2011; Kidney international. 79(10) 1090-8. PMID: 21289599 | PMCID: PMC3155206

Kennedy AJ, Mathews TP, Kharel Y, Field SD, Moyer ML, East JE, Houck JD, Lynch KR, Macdonald TL, Development of amidine-based sphingosine kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in human leukemia cells., 2011; Journal of medicinal chemistry. 54(10) 3524-48. PMID: 21495716 | PMCID: PMC3119570

Kennedy PC, Zhu R, Huang T, Tomsig JL, Mathews TP, David M, Peyruchaud O, Macdonald TL, Lynch KR, Characterization of a sphingosine 1-phosphate receptor antagonist prodrug., 2011; The Journal of pharmacology and experimental therapeutics. 338(3) 879-89. PMID: 21632869 | PMCID: PMC3164350

Kharel Y, Mathews TP, Gellett AM, Tomsig JL, Kennedy PC, Moyer ML, Macdonald TL, Lynch KR, Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate., 2011; The Biochemical journal. 440(3) 345-53. PMID: 21848514 | PMCID: PMC3443603

Raje MR, Knott K, Kharel Y, Bissel P, Lynch KR, Santos WL, Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors., 2011; Bioorganic & medicinal chemistry. 20(1) 183-94. PMID: 22137932 | PMCID: NIHMS338841

East JE, Carter KM, Kennedy PC, Schulte NA, Toews ML, Lynch KR, Macdonald TL, Development of a phosphatase-resistant, L-tyrosine derived LPA1/LPA3 dual antagonist., 2011; MedChemComm. 2(4) 325-330. PMID: 22180836 | PMCID: PMC3237054

Mathews TP, Kennedy AJ, Kharel Y, Kennedy PC, Nicoara O, Sunkara M, Morris AJ, Wamhoff BR, Lynch KR, Macdonald TL, Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors., 2010; Journal of medicinal chemistry. 53(7) 2766-78. PMID: 20205392 | PMCID: PMC2875079

Bajwa A, Jo SK, Ye H, Huang L, Dondeti KR, Rosin DL, Haase VH, Macdonald TL, Lynch KR, Okusa MD, Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury., 2010; Journal of the American Society of Nephrology : JASN. 21(6) 955-65. PMID: 20338995 | PMCID: PMC2900956

East JE, Kennedy AJ, Tomsig JL, De Leon AR, Lynch KR, Macdonald TL, Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX)., 2010; Bioorganic & medicinal chemistry letters. 20(23) 7132-6. PMID: 20951039 | PMCID: PMC2975792

Foss FW, Mathews TP, Kharel Y, Kennedy PC, Snyder AH, Davis MD, Lynch KR, Macdonald TL, Synthesis and biological evaluation of sphingosine kinase substrates as sphingosine-1-phosphate receptor prodrugs., 2009; Bioorganic & medicinal chemistry. 17(16) 6123-36. PMID: 19632123 | PMCID: PMC2793099

Petrie Aronin CE, Sefcik LS, Tholpady SS, Tholpady A, Sadik KW, Macdonald TL, Peirce SM, Wamhoff BR, Lynch KR, Ogle RC, Botchwey EA, FTY720 promotes local microvascular network formation and regeneration of cranial bone defects., 2009; Tissue engineering. Part A. 16(6) 1801-9. PMID: 20038198 | PMCID: PMC2949231

Tomsig JL, Snyder AH, Berdyshev EV, Skobeleva A, Mataya C, Natarajan V, Brindley DN, Lynch KR, Lipid phosphate phosphohydrolase type 1 (LPP1) degrades extracellular lysophosphatidic acid in vivo., 2009; The Biochemical journal. 419(3) 611-8. PMID: 19215222 | PMCID: PMC2677185

Okusa MD, Lynch KR, Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury., 2009; Drug discovery today. Disease mechanisms. 4(1) 55-59. PMID: 19448841 | PMCID: PMC2682423

Rivera-Lopez CM, Tucker AL, Lynch KR, Lysophosphatidic acid (LPA) and angiogenesis., 2008; Angiogenesis. 11(3) 301-10. PMID: 18504643 | PMCID: PMC2677190

Jo SK, Bajwa A, Awad AS, Lynch KR, Okusa MD, Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease., 2008; Kidney international. 73(11) 1220-30. PMID: 18322542 | PMCID: PMC2614447

Hughes JE, Srinivasan S, Lynch KR, Proia RL, Ferdek P, Hedrick CC, Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages., 2008; Circulation research. 102(8) 950-8. PMID: 18323526 | PMCID: PMC2875063

Wamhoff BR, Lynch KR, Macdonald TL, Owens GK, Sphingosine-1-phosphate receptor subtypes differentially regulate smooth muscle cell phenotype., 2008; Arteriosclerosis, thrombosis, and vascular biology. 28(8) 1454-61. PMID: 18535287 | PMCID: PMC2605659

Lynch KR, Macdonald TL, Sphingosine 1-phosphate chemical biology., 2008; Biochimica et biophysica acta. 1781(9) 508-12. PMID: 18638568 | PMCID: PMC3412363

Jo SK, Bajwa A, Ye H, Vergis AL, Awad AS, Kharel Y, Lynch KR, Okusa MD, Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury., 2008; Kidney international. 75(2) 167-75. PMID: 18971925 | PMCID: PMC2646633

Cui P, McCalmont WF, Tomsig JL, Lynch KR, Macdonald TL, alpha- and beta-substituted phosphonate analogs of LPA as autotaxin inhibitors., 2007; Bioorganic & medicinal chemistry. 16(5) 2212-25. PMID: 18082408 | PMCID: PMC2907913

Cui P, Tomsig JL, McCalmont WF, Lee S, Becker CJ, Lynch KR, Macdonald TL, Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors., 2007; Bioorganic & medicinal chemistry letters. 17(6) 1634-40. PMID: 17257836 | PMCID: NIHMS20052

Zhu R, Snyder AH, Kharel Y, Schaffter L, Sun Q, Kennedy PC, Lynch KR, Macdonald TL, Asymmetric synthesis of conformationally constrained fingolimod analogues--discovery of an orally active sphingosine 1-phosphate receptor type-1 agonist and receptor type-3 antagonist., 2007; Journal of medicinal chemistry. 50(25) 6428-35. PMID: 17994678 | PMCID: PMC2895489

Srinivasan S, Bolick DT, Lukashev D, Lappas C, Sitkovsky M, Lynch KR, Hedrick CC, Sphingosine-1-phosphate reduces CD4+ T-cell activation in type 1 diabetes through regulation of hypoxia-inducible factor short isoform I.1 and CD69., 2007; Diabetes. 57(2) 484-93. PMID: 18003758

Awad AS, Ye H, Huang L, Li L, Foss FW, Macdonald TL, Lynch KR, Okusa MD, Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney., 2006; American journal of physiology. Renal physiology. 290(6) F1516-24. PMID: 16403835

Foss FW, Snyder AH, Davis MD, Rouse M, Okusa MD, Lynch KR, Macdonald TL, Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists., 2006; Bioorganic & medicinal chemistry. 15(2) 663-77. PMID: 17113298 | PMCID: PMC1963459