Kevin R. Lynch

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  • Phone: 434-924-2840
  • Fax: 434-982-3878

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, Immunology, Molecular Pharmacology, Translational Science

Research Interests

Chemical biology of sphingosine 1-phosphate

Research Description

Our research investigates the biology of the lipid mediator, sphingosine 1-phosphate (S1P). S1P concentration gradients are known to influence immune cell positioning. Indeed, S1P type 1 receptor agonist drugs are immunosuppressive by virtue of down regulating cell surface S1P1 receptors and thereby interdicting lymphocyte egress from lymph nodes to efferent lymph. While a set of S1P1 receptor modulator drugs are used clinically for treating autoimmune diseases, the class is beset by adverse events such as first dose bradycardia.
An alternative to masking the existence of S1P gradients from lymphocytes is to reshape the S1P gradients by inhibiting the S1P transporter, Spns2. Ideally, drugs blocking the release of cellular S1P will capture the efficacy of S1P receptor modulators with lessened adverse events. To test this idea, we are discovering and characterizing small molecule Spns2 inhibitors. Our inhibitors are proving useful as chemical probes to increase understanding of S1P signaling and may provide a path to developing a S1P transport blocking drug.

Personal Statement

Our research investigates the biology of the lipid mediator, sphingosine 1-phosphate (S1P). S1P concentration gradients are known to influence immune cell positioning. Indeed, S1P type 1 receptor agonist drugs are immunosuppressive by virtue of down regulating cell surface S1P1 receptors and thereby interdicting lymphocyte egress from lymph nodes to efferent lymph. While a set of S1P1 receptor modulator drugs are used clinically for treating autoimmune diseases, the class is beset by adverse events such as first dose bradycardia.
An alternative to masking the existence of S1P gradients from lymphocytes is to reshape the S1P gradients by inhibiting the S1P transporter, Spns2. Ideally, drugs blocking the release of cellular S1P will capture the efficacy of S1P receptor modulators with lessened adverse events. To test this idea, we are discovering and characterizing small molecule Spns2 inhibitors. Our inhibitors are proving useful as chemical probes to increase understanding of S1P signaling and may provide a path to developing a S1P transport blocking drug.

Training

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

Selected Publications

2024

Foster, D. J., Dunnavant, K., Shrader, C. W., LoPresti, M., Seay, S., Kharel, Y., . . . Santos, W. L. (2024). Discovery of Potent, Orally Bioavailable Sphingosine-1-Phosphate Transporter (Spns2) Inhibitors. JOURNAL OF MEDICINAL CHEMISTRY. doi:10.1021/acs.jmedchem.4c00879

Kharel, Y., Huang, T., Dunnavant, K., Foster, D., Souza, G., Nimchuk, K. E., . . . Lynch, K. R. (2024). Assessing Spns2-dependent S1P Transport as a Prospective Therapeutic Target.. bioRxiv. doi:10.1101/2024.03.26.586765

2023

Busey, G. W., Manjegowda, M. C., Huang, T., Iobst, W. H., Naphade, S. S., Kennedy, J. A., . . . Desai, B. N. (2023). Analogs of FTY720 inhibit TRPM7 but not S1PRs and exert multimodal anti-inflammatory effects. JOURNAL OF GENERAL PHYSIOLOGY, 156(1). doi:10.1085/jgp.202313419

Kharel, Y., Huang, T., Santos, W. L., & Lynch, K. R. (2023). Assay of Sphingosine 1-phosphate Transporter Spinster Homolog 2 (Spns2) Inhibitors. SLAS DISCOVERY, 28(6), 284-287. doi:10.1016/j.slasd.2023.07.001

Burgio, A. L., Shrader, C. W., Kharel, Y., Huang, T., Salamoun, J. M., Lynch, K. R., & Santos, W. L. (2023). 2-Aminobenzoxazole Derivatives as Potent Inhibitors of the Sphingosine-1-Phosphate Transporter Spinster Homolog 2 (Spns2). JOURNAL OF MEDICINAL CHEMISTRY, 66(8), 5873-5891. doi:10.1021/acs.jmedchem.3c00149

2022

Tanaka, S., Zheng, S., Kharel, Y., Fritzemeier, R. G., Huang, T., Foster, D., . . . Okusa, M. D. (2022). Sphingosine 1-phosphate signaling in perivascular cells enhances inflammation and fibrosis in the kidney. SCIENCE TRANSLATIONAL MEDICINE, 14(658). doi:10.1126/scitranslmed.abj2681

Pashikanti, S., Foster, D. J., Kharel, Y., Brown, A. M., Bevan, D. R., Lynch, K. R., & Santos, W. L. (2022). Sphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analogues. ACS BIO & MED CHEM AU, 2(5), 469-489. doi:10.1021/acsbiomedchemau.2c00017

Oyewole, O. O., Dunnavant, K., Bhattarai, S., Kharel, Y., Lynch, K. R., Santos, W. L., & Reid, S. P. (2022). A Novel Sphingosine Kinase Inhibitor Suppresses Chikungunya Virus Infection. VIRUSES-BASEL, 14(6). doi:10.3390/v14061123

Fritzemeier, R., Foster, D., Peralta, A., Payette, M., Kharel, Y., Huang, T., . . . Santos, W. L. (2022). Discovery of In Vivo Active Sphingosine-1-phosphate Transporter (Spns2) Inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 65(11), 7656-7681. doi:10.1021/acs.jmedchem.1c02171

2020

Congdon, M., Fritzemeier, R. G., Kharel, Y., Brown, A. M., Serbulea, V., Bevan, D. R., . . . Santos, W. L. (2021). Probing the substitution pattern of indole-based scaffold reveals potent and selective sphingosine kinase 2 inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 212. doi:10.1016/j.ejmech.2020.113121

Li, H., Sibley, C. D., Kharel, Y., Huang, T., Brown, A. M., Wonilowicz, L. G., . . . Santos, W. L. (2021). Lipophilic tail modifications of 2-(hydroxymethyl)pyrrolidine scaffold reveal dual sphingosine kinase 1 and 2 inhibitors. BIOORGANIC & MEDICINAL CHEMISTRY, 30. doi:10.1016/j.bmc.2020.115941

Kharel, Y., Huang, T., Salamon, A., Harris, T. E., Santos, W. L., & Lynch, K. R. (2020). Mechanism of sphingosine 1-phosphate clearance from blood. BIOCHEMICAL JOURNAL, 477(5), 925-935. doi:10.1042/BCJ20190730

Sibley, C. D., Morris, E. A., Kharel, Y., Brown, A. M., Huang, T., Bevan, D. R., . . . Santos, W. L. (2020). Discovery of a Small Side Cavity in Sphingosine Kinase 2 that Enhances Inhibitor Potency and Selectivity. JOURNAL OF MEDICINAL CHEMISTRY, 63(3), 1178-1198. doi:10.1021/acs.jmedchem.9b01508

2018

Adamiak, M., Chelvarajan, L., Lynch, K. R., Santos, W. L., Abdel-Latif, A., & Ratajczak, M. Z. (2018). 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.. Oncotarget, 9(75), 34189. doi:10.18632/oncotarget.26195

Mehaffey, J. H., Charles, E. J., Narahari, A. K., Schubert, S., Laubach, V. E., Teman, N. R., . . . Sharma, A. K. (2018). Increasing circulating sphingosine-1-phosphate attenuates lung injury during ex vivo lung perfusion. JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 156(2), 910-917. doi:10.1016/j.jtcvs.2018.02.090

Cao, R., Li, J., Kharel, Y., Zhang, C., Morris, E., Santos, W. L., . . . Hu, S. (2018). Photoacoustic microscopy reveals the hemodynamic basis of sphingosine 1-phosphate-induced neuroprotection against ischemic stroke. THERANOSTICS, 8(22), 6111-6120. doi:10.7150/thno.29435

Kharel, Y., Agah, S., Huang, T., Mendelson, A. J., Eletu, O. T., Barkey-Bircannl, P., . . . Lynch, K. R. (2018). Saccharomyces cerevisiae as a platform for assessing sphingolipid lipid kinase inhibitors. PLOS ONE, 13(4). doi:10.1371/journal.pone.0192179

2017

Adamiak, M., Chelvarajan, L., Lynch, K. R., Santos, W. L., Abdel-Latif, A., & Ratajczak, M. Z. (2017). 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.. Oncotarget, 8(39), 65588-65600. doi:10.18632/oncotarget.19514

Adamiak, M., Chelvarajan, L., Lynch, K. R., Santos, W. L., Abdel-Latif, A., & Ratajczak, M. Z. (2017). 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. ONCOTARGET, 8(39), 65588-65600. doi:10.18632/oncotarget.19514

Childress, E. S., Kharel, Y., Brown, A. M., Bevan, D. R., Lynch, K. R., & Santos, W. L. (2017). Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity. JOURNAL OF MEDICINAL CHEMISTRY, 60(9), 3933-3957. doi:10.1021/acs.jmedchem.7b00233

2016

Bajwa, A., Huang, L., Kurmaeva, E., Ye, H., Dondeti, K. R., Chroscicki, P., . . . Okusa, M. D. (2017). Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-γ. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 28(4), 1145-1161. doi:10.1681/ASN.2016030306

Lynch, K. R., Thorpe, S. B., & Santos, W. L. (2016). Sphingosine kinase inhibitors: a review of patent literature (2006-2015). EXPERT OPINION ON THERAPEUTIC PATENTS, 26(12), 1409-1416. doi:10.1080/13543776.2016.1226282

Perry, H. M., Huang, L., Ye, H., Liu, C., Sung, S. -S. J., Lynch, K. R., . . . Okusa, M. D. (2016). Endothelial Sphingosine 1-Phosphate Receptor-1 Mediates Protection and Recovery from Acute Kidney Injury. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 27(11), 3383-3393. doi:10.1681/ASN.2015080922

Houck, J. D., Dawson, T. K., Kennedy, A. J., Kharel, Y., Naimon, N. D., Field, S. D., . . . Macdonald, T. L. (2016). Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles. ACS MEDICINAL CHEMISTRY LETTERS, 7(5), 487-492. doi:10.1021/acsmedchemlett.6b00002

Congdon, M. D., Kharel, Y., Brown, A. M., Lewis, S. N., Bevan, D. R., Lynch, K. R., & Santos, W. L. (2016). Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene-Based Sphingosine Kinase 2 Inhibitors. ACS MEDICINAL CHEMISTRY LETTERS, 7(3), 229-234. doi:10.1021/acsmedchemlett.5b00304

2015

Kharel, Y., Morris, E. A., Congdon, M. D., Thorpe, S. B., Tomsig, J. L., Santos, W. L., & Lynch, K. R. (2015). Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 355(1), 23-31. doi:10.1124/jpet.115.225862

Stone, M. L., Sharma, A. K., Zhao, Y., Charles, E. J., Huerter, M. E., Johnston, W. F., . . . Laubach, V. E. (2015). Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury. AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 308(12), L1245-L1252. doi:10.1152/ajplung.00302.2014

Congdon, M. D., Childress, E. S., Patwardhan, N. N., Gumkowski, J., Morris, E. A., Kharel, Y., . . . Santos, W. L. (2015). Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 25(21), 4956-4960. doi:10.1016/j.bmcl.2015.03.041

Patwardhan, N. N., Morris, E. A., Kharel, Y., Raje, M. R., Gao, M., Tomsig, J. L., . . . Santos, W. L. (2015). Structure-Activity Relationship Studies and in Vivo Activity of Guanidine-Based Sphingosine Kinase Inhibitors: Discovery of SphK1-and SphK2-Selective Inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 58(4), 1879-1899. doi:10.1021/jm501760d

2014

Santos, W. L., & Lynch, K. R. (2015). Drugging Sphingosine Kinases. ACS CHEMICAL BIOLOGY, 10(1), 225-233. doi:10.1021/cb5008426

Bajwa, A., Rosin, D. L., Chroscicki, P., Lee, S., Dondeti, K., Ye, H., . . . Okusa, M. D. (2015). Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 26(4), 908-925. doi:10.1681/ASN.2013121351

Ogle, M. E., Sefcik, L. S., Awojoodu, A. O., Chiappa, N. F., Lynch, K., Peirce-Cottler, S., & Botchwey, E. A. (2014). Engineering in vivo gradients of sphingosine-1-phosphate receptor ligands for localized microvascular remodeling and inflammatory cell positioning. ACTA BIOMATERIALIA, 10(11), 4704-4714. doi:10.1016/j.actbio.2014.08.007

2012

Kharel, Y., Raje, M., Gao, M., Gellett, A. M., Tomsig, J. L., Lynch, K. R., & Santos, W. L. (2012). Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate. BIOCHEMICAL JOURNAL, 447, 149-157. doi:10.1042/BJ20120609

Bajwa, A., Huang, L., Ye, H., Dondeti, K., Song, S., Rosin, D. L., . . . Okusa, M. D. (2012). Dendritic Cell Sphingosine 1-Phosphate Receptor-3 Regulates Th1-Th2 Polarity in Kidney Ischemia-Reperfusion Injury. JOURNAL OF IMMUNOLOGY, 189(5), 2584-2596. doi:10.4049/jimmunol.1200999

Gellett, A. M., Kharel, Y., Sunkara, M., Morris, A. J., & Lynch, K. R. (2012). Biosynthesis of alkyl lysophosphatidic acid by diacylglycerol kinases. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 422(4), 758-763. doi:10.1016/j.bbrc.2012.05.077

Lynch, K. R. (2012). Building a better sphingosine kinase-1 inhibitor.. The Biochemical journal, 444(1), e1-e2. doi:10.1042/bj20120567

Knott, K., Kharel, Y., Raje, M. R., Lynch, K. R., & Santos, W. L. (2012). Effect of alkyl chain length on sphingosine kinase 2 selectivity. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 22(22), 6817-6820. doi:10.1016/j.bmcl.2012.01.050

2011

Kharel, Y., Mathews, T. P., Gellett, A. M., Tomsig, J. L., Kennedy, P. C., Moyer, M. L., . . . Lynch, K. R. (2011). Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate. BIOCHEMICAL JOURNAL, 440, 345-353. doi:10.1042/BJ20110817

Raje, M. R., Knott, K., Kharel, Y., Bissel, P., Lynch, K. R., & Santos, W. L. (2012). Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors. BIOORGANIC & MEDICINAL CHEMISTRY, 20(1), 183-194. doi:10.1016/j.bmc.2011.11.011

Callihan, P., Zitomer, N. C., Stoeling, M. V., Kennedy, P. C., Lynch, K. R., Riley, R. T., & Hooks, S. B. (2012). Distinct generation, pharmacology, and distribution of sphingosine 1-phosphate and dihydro-sphingosine 1-phosphate in human neural progenitor cells. FASEB JOURNAL, 26. Retrieved from https://www.webofscience.com/

Kennedy, P. C., Zhu, R., Macdonald, T. L., & Lynch, K. R. (2008). Characterization of a Sphingosine-1-phosphate Receptor Antagonist. FASEB JOURNAL, 22. Retrieved from https://www.webofscience.com/

Kennedy, A. J., Mathews, T. P., Kharel, Y., Field, S. D., Moyer, M. L., East, J. E., . . . Macdonald, T. L. (2011). Development of Amidine-Based Sphingosine Kinase 1 Nanomolar Inhibitors and Reduction of Sphingosine 1-Phosphate in Human Leukemia Cells. JOURNAL OF MEDICINAL CHEMISTRY, 54(10), 3524-3548. doi:10.1021/jm2001053

Awad, A. S., Rouse, M. D., Khutsishvili, K., Huang, L., Bolton, W. K., Lynch, K. R., & Okusa, M. D. (2011). Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes. KIDNEY INTERNATIONAL, 79(10), 1090-1098. doi:10.1038/ki.2010.544

Kharel, Y., Mathews, T. P., Kennedy, A. J., Houck, J. D., Macdonald, T. L., & Lynch, K. R. (2011). A rapid assay for assessment of sphingosine kinase inhibitors and substrates. ANALYTICAL BIOCHEMISTRY, 411(2), 230-235. doi:10.1016/j.ab.2011.01.003

2010

Chun, J., Hla, T., Lynch, K. R., Spiegel, S., & Moolenaar, W. H. (2010). International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature. PHARMACOLOGICAL REVIEWS, 62(4), 579-587. doi:10.1124/pr.110.003111

Sefcik, L. S., Aronin, C. E. P., Awojoodu, A. O., Shin, S. J., Mac Gabhann, F., MacDonald, T. L., . . . Botchwey, E. A. (2011). Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth. TISSUE ENGINEERING PART A, 17(5-6), 617-629. doi:10.1089/ten.tea.2010.0404

Aronin, C. E. P., Sefcik, L. S., Tholpady, S. S., Tholpady, A., Sadik, K. W., Macdonald, T. L., . . . Botchwey, E. A. (2010). FTY720 Promotes Local Microvascular Network Formation and Regeneration of Cranial Bone Defects. TISSUE ENGINEERING PART A, 16(6), 1801-1809. doi:10.1089/ten.tea.2009.0539

Derecki, N. C., Cardani, A. N., Yang, C. H., Quinnies, K. M., Crihfield, A., Lynch, K. R., & Kipnis, J. (2010). Regulation of learning and memory by meningeal immunity: a key role for IL-4. JOURNAL OF EXPERIMENTAL MEDICINE, 207(5), 1067-1080. doi:10.1084/jem.20091419

Mathews, T. P., Kennedy, A. J., Kharel, Y., Kennedy, P. C., Nicoara, O., Sunkara, M., . . . Macdonald, T. L. (2010). Discovery, Biological Evaluation, and Structure-Activity Relationship of Amidine Based Sphingosine Kinase Inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 53(7), 2766-2778. doi:10.1021/jm901860h

Bajwa, A., Jo, S. -K., Ye, H., Huang, L., Dondeti, K. R., Rosin, D. L., . . . Okusa, M. D. (2010). Activation of Sphingosine-1-Phosphate 1 Receptor in the Proximal Tubule Protects Against Ischemia-Reperfusion Injury. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 21(6), 955-965. doi:10.1681/ASN.2009060662

Ma, B., Guckian, K. M., Lin, E. Y. -S., Lee, W. -C., Scott, D., Kumaravel, G., . . . Yang, C. (2010). Stereochemistry-activity relationship of orally active tetralin S1P agonist prodrugs. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 20(7), 2264-2269. doi:10.1016/j.bmcl.2010.02.006

Derecki, N., Cardani, A., Quinnies, K., Crihfield, A., Lynch, K., & Kipnis, J. (2010). Meningeal Immunity, Learning and Memory, and IL-4: Do T cells Make You Smart?. JOURNAL OF IMMUNOLOGY, 184. Retrieved from https://www.webofscience.com/

Wamhoff, B. R., Matthews, T., Hogan, J., Morris, A., Karel, Y., Macdonald, T., & Lynch, K. R. (2010). Sphingosine kinase 1 is required for smooth muscle cell phenotypic modulation in response to vascular injury.. FASEB JOURNAL, 24. Retrieved from https://www.webofscience.com/

Bajwa, A., Jo, S. -K., Ye, H., Huang, L., Dondeti, K. R., Rosin, D. L., . . . Okusa, M. D. (2010). ACTIVATION OF PROXIMAL TUBULE SPIIINGOSINE 1-PHOSPHATE RECEPTOR 1 PROTECTS KIDNEYS FROM ISCHEMIA REPERFUSION INJURY INDEPENDENT OF LYMPHOCYTES. AMERICAN JOURNAL OF KIDNEY DISEASES, 55(4), A42. Retrieved from https://www.webofscience.com/