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Karen Leach

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Karen L. Leach is an American biochemist with extensive drug discovery experience in large pharmaceutical research laboratories. Her expertise in molecular pharmacology, signal transduction and protein kinases, has been used to establish mechanisms of toxicity for therapeutics such as the novel antibiotic linezolid (Zyvox).

Early life and education

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Born in Akron, Ohio to Glenn and Margaret Leach, she was the third of four daughters.[1] Leach graduated as valedictorian from Revere High School in Richfield Ohio in 1973[2] and attended Ohio Wesleyan University, graduating magna cum laude with a BA in biochemistry, in 1977.[citation needed] In the laboratory of William B. Pratt at the University of Michigan, Leach did graduate research focused on the regulation of glucocorticoid hormone action and received her Ph. D. from the department of pharmacology in 1981.[3]

Scientific contributions

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Leach continued her scientific research as a National Research Service Award Postdoctoral Fellow at the National Institutes of Health (NIH) where she studied the cancer-related phorbol estrogen receptor in the laboratory of Peter Blumberg. Publications from the laboratory of Yasutomi Nishizuka on a newly discovered enzyme named protein kinase C (PKC)[4] that was stimulated by phorbol ester led Leach to the realization that the phorbol estrogen receptor she was studying was in fact PKC.[5] These fundamental discoveries in a burgeoning new field fueled Leach’s passion for kinases and in the broader field of signal transduction.

Leach moved on to research in the pharmaceutical industry (at The Upjohn Company, which became the Pharmacia Corp and eventually at Pfizer, Inc.) where her expertise with kinases and signal transduction launched her career, enabling her to lead discovery teams in the fields of oncology,[6] Alzheimer Disease,[7] and calcium signaling,[8] leading to her application of these scientific insights to understanding of drug safety issues, particularly for the novel class of oxazolidinone antibiotics such as linezolid. The approval of Zyvox to the antibiotic armentarium in 2000[9] was hailed as a much needed breakthrough in addressing the antibiotic resistance crisis. However safety concerns during prolonged usage in some patients highlighted a need for understanding the molecular basis of the toxicity in humans in order to design safer next- generation antibiotics. Given the mechanism of action for oxazolidinones as protein translation disruptors in bacterial pathogens and the bacterial ancestry of mitochondria,[10] Leach began pursuing research into the hypothesis that the toxicity to human cells was linked to inhibition of mitochondrial protein synthesis. Her lab generated significant amounts of data implicating the role of mitochondrial protein synthesis inhibition in mammalian cellular toxicity. Their conclusive experiment was the direct demonstration of the absence of oxazolidinone toxicity in rho 0 cells,[11] which contain mitochondria, but lack mitochondrial DNA and thus are unable to synthesize proteins.[12] By showing mitochondrial protein synthesis was the link to Zyvox cytotoxicity in human cells, this research led to important advances in antibiotic safety and utilization of in vitro assays to predict in vivo toxicity.

Leach went on to conduct cross-disciplinary efforts within Pfizer using chemistry-cell biology approaches to predict safety issues in vitro, long before the drug leads were tested in animals. Her kinase expertise helped connect scientists across a wide array of therapeutic discovery efforts within Pfizer[13][14] where she led a coordinated kinase safety effort across this large multinational corporation. Tapping into her kinase expertise in drug discovery efforts, she became a scientific liaison to the Division of Signal Transduction Therapy at the University of Dundee School of Life Sciences. Her research at Pfizer continued to focus on in vitro predictions of compound safety, for kinase inhibitors as well as other drug discovery candidates and therapeutic agents.

Leach’s scientific career included positions at increasing levels of Research Scientist levels, Associate Research Fellow, and leader of several discovery teams before being named Director of Academic Research Collaborations at Pfizer’s Centers for Therapeutic Innovations in Boston, MA. She now serves as an independent consultant, using her over 30 years of expertise to advise clients in various aspects of pharmaceutical discovery.

Professional activities

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2017–present Member, Washington University Center for Drug Discovery External Advisory Committee

2012-2015 Pfizer scientific liaison, University of Dundee DSTT Consortium

2004-2006 Contributor, Zyvox World Wide Medical team oxazolidinone external research grant program

1994-2003 Adjunct Assistant Professor, Michigan State University, Biochemistry Department

2002-2003 Grant Reviewer, Washington University-Pharmacia Biomedical Grants

2001 Co-organizer, Signaling Symposium for MI Regional ACS meeting

1996-1998 Grant Reviewer, US Army Women’s Health Research Oncology Program

1996-1999 Advisor, Michigan State University-NIH Mass Spectrometry Advisory Committee

1990-1995 Grant reviewer, Michigan Heart Association Grant Review Committee

1990 Co-chair, Sixth International Symposium on Cellular Endocrinology

1990-1994 Associate editor, Journal of Immunology

Representative publications

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  • Zhang X, Scialis RJ, Feng B, Leach K. Detection of statin cytotoxicity is increased in cells expressing the OATP1B1 transporter. Toxicol Sci. 2013;134(1):73‐82. \[14]
  • Leach, K.L., Swaney, S.M., Colca, J.R., McDonald, W.G., Blinn, J.R., Shinabarger, D., Xiong, L., Mankin, A. S. The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria. Molecular Cell 26: 393-402, 2007.[15]
  • Nagiec, Eva E.; Wu, Luping; Swaney, Steve M.; Chosay, John G.; Ross, Daniel E.; Brieland, Joan K.; Leach, Karen L. Oxazolidinones inhibit cellular proliferation via inhibition of mitochondrial protein synthesis. Antimicrobial Agents and Chemotherapy 49, 3896-3902, 2005.[12]
  • Clare, P.M, Poorman, R.A., Kelly, L.C., Watenpaugh, K.D., Leach, K.L. Cdk2 and cdk5 act by a random, uncompetitive kinetic mechanism. J. Biol. Chem. 276:48292-48299, 2001.[16]
  • Scott, J.E., Ruff, V.A., Leach, K.L. Dynamic equilibrium between calcineurin and kinase activities regulates the phosphorylation state and localization of the nuclear factor of activated T-cells. Biochem. J. 324: 597-603, 1997[8]
  • Leach, K.L., Ruff, V.A., Jarpe, M.B., Adams, L.D., Fabbro, D., and Raben, D.M. Alpha-Thrombin stimulates nuclear diglyceride levels and differential nuclear localization of protein kinase C isozymes in IIC9 cells. J. Biological Chemistry 267:21816-21822, 1992.[17]
  • Leach, K.L., Powers, E.A., Ruff, V.A., Jaken, S. and Kaufmann, S. Type 3 protein kinase C localization to the nuclear envelope of phorbol ester-treated NIH 3T3 cells. J. Cell. Biol., 109:685-695, 1989.[18]
  • Leach, K.L. and Blumberg, P.M. Modulation of protein kinase C activity and [3H] phorbol 12,13-dibutyrate binding by various tumor promoters. Cancer Res., 45:1958-1963, 1985.[19]
  • Leach, K.L., James, M.L. and Blumberg, P.M. Characterization of a specific phorbol ester apo-receptor in mouse brain cytosol. Proc. Natl. Acad. Sci. USA, 80:4208-4212,1983.[20]
  • Leach, K.L., Grippo, J.F., Housley, P.R., Dahmer, M.K., Salive, M.E. and Pratt, W.B. Characteristics of an endogenous glucocorticoid receptor stabilizing factor. J. Biol. Chem., 257:381-388, 1982[21]

References

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  1. ^ "Glenn Leach". The Daily Record. Retrieved 2020-07-22.
  2. ^ "Class History of Revere High School 1970–1979" (PDF). Retrieved 16 May 2021.
  3. ^ "External Advisory Committee Members – Center for Drug Discovery". Retrieved 2023-04-03.
  4. ^ Nakamura, Shun-ichi; Yamamura, Hirohei (2010-08-01). "Yasutomi Nishizuka: Father of protein kinase C". The Journal of Biochemistry. 148 (2): 125–130. doi:10.1093/jb/mvq066. ISSN 0021-924X. PMID 20668066.
  5. ^ Leach, KL; Blumberg, PM (1985). "Modulation of protein kinase C activity and [3H]phorbol 12,13-dibutyrate binding by various tumor promoters in mouse brain cytosol" (PDF). Cancer Res. 45 (5): 1958‐1963. PMID 3157441.
  6. ^ Leach, Karen L.; Powers, Elaine A.; Mayo, Judy K.; Abraham, Irene; Burnett, Bonnie-Ann; Groppi, Vincent E. (1987). "Phorbol myristate acetate inhibits growth in S49 cells: Isolation of resistant variants". Journal of Cellular Physiology. 132 (3): 463–472. doi:10.1002/jcp.1041320308. ISSN 0021-9541. PMID 3477548. S2CID 40507468.
  7. ^ Abraham, I.; Sampson, K. E.; Powers, E. A.; Mayo, J. K.; Ruff, V. A.; Leach, K. L. (1991). "Increased PKA and PKC activities accompany neuronal differentiation of NT2/D1 cells". Journal of Neuroscience Research. 28 (1): 29–39. doi:10.1002/jnr.490280104. ISSN 1097-4547. PMID 2041056. S2CID 12067365.
  8. ^ a b Scott, John E.; Ruff, Valerie A.; Leach, Karen L. (1997-06-01). "Dynamic equilibrium between calcineurin and kinase activities regulates the phosphorylation state and localization of the nuclear factor of activated T-cells". Biochemical Journal. 324 (2): 597–603. doi:10.1042/bj3240597. ISSN 0264-6021. PMC 1218471. PMID 9182723.
  9. ^ "Drug Approval Package". FDA. Retrieved 16 May 2021.
  10. ^ Gray, Michael W. (2012). "Mitochondrial Evolution". Cold Spring Harbor Perspectives in Biology. 4 (9): a011403. doi:10.1101/cshperspect.a011403. ISSN 1943-0264. PMC 3428767. PMID 22952398.
  11. ^ King, M.; Attardi, G (1989-10-27). "Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation". Science. 246 (4929): 500–503. Bibcode:1989Sci...246..500K. doi:10.1126/science.2814477. ISSN 0036-8075. PMID 2814477.
  12. ^ a b Nagiec, Eva E.; Wu, Luping; Swaney, Steve M.; Chosay, John G.; Ross, Daniel E.; Brieland, Joan K.; Leach, Karen L. (2005). "Oxazolidinones Inhibit Cellular Proliferation via Inhibition of Mitochondrial Protein Synthesis". Antimicrobial Agents and Chemotherapy. 49 (9): 3896–3902. doi:10.1128/AAC.49.9.3896-3902.2005. ISSN 0066-4804. PMC 1195406. PMID 16127068.
  13. ^ Magee, Thomas V.; Brown, Matthew F.; Starr, Jeremy T.; Ackley, David C.; Abramite, Joseph A.; Aubrecht, Jiri; Butler, Andrew; Crandon, Jared L.; Dib-Hajj, Fadia; Flanagan, Mark E.; Granskog, Karl (2013-06-27). "Discovery of Dap-3 Polymyxin Analogues for the Treatment of Multidrug-Resistant Gram-Negative Nosocomial Infections". Journal of Medicinal Chemistry. 56 (12): 5079–5093. doi:10.1021/jm400416u. ISSN 0022-2623. PMID 23735048.
  14. ^ a b Zhang, Xun; Scialis, Renato J.; Feng, Bo; Leach, Karen (2013). "Detection of Statin Cytotoxicity Is Increased in Cells Expressing the OATP1B1 Transporter". Toxicological Sciences. 134 (1): 73–82. doi:10.1093/toxsci/kft085. ISSN 1096-6080. PMID 23564645.
  15. ^ Leach, Karen L.; Swaney, Steven M.; Colca, Jerry R.; McDonald, William G.; Blinn, James R.; Thomasco, Lisa M.; Gadwood, Robert C.; Shinabarger, Dean; Xiong, Liqun; Mankin, Alexander S. (2007). "The Site of Action of Oxazolidinone Antibiotics in Living Bacteria and in Human Mitochondria". Molecular Cell. 26 (3): 393–402. doi:10.1016/j.molcel.2007.04.005. PMID 17499045.
  16. ^ Clare, PM; Poorman, RA; Kelly, LC; Watenpaugh, KD; Bannow, CA; Leach, KL (2001). "The Cyclin-dependent Kinases cdk2 and cdk5 Act by a Random, Anticooperative Kinetic Mechanism". J Biol Chem. 276 (51): 48292–48299. doi:10.1074/jbc.M102034200. PMID 11604388. S2CID 33406123.
  17. ^ Jarpe, Matt B.; Leach, Karen L.; Raben, Daniel M. (1994-01-18). ".alpha.-Thrombin-induced nuclear sn-1,2-diacylglycerols are derived from phosphatidylcholine hydrolysis in cultured fibroblasts". Biochemistry. 33 (2): 526–534. doi:10.1021/bi00168a018. ISSN 0006-2960. PMID 8286382.
  18. ^ Leach, K L; Powers, E A; Ruff, V A; Jaken, S; Kaufmann, S (1989-08-01). "Type 3 protein kinase C localization to the nuclear envelope of phorbol ester-treated NIH 3T3 cells". The Journal of Cell Biology. 109 (2): 685–695. doi:10.1083/jcb.109.2.685. ISSN 0021-9525. PMC 2115724. PMID 2668302.
  19. ^ Leach, KL; Blumberg, PM (1985). "Modulation of Protein Kinase C Activity and [3H]phorbol 12,13-dibutyrate Binding by Various Tumor Promoters in Mouse Brain Cytosol". Cancer Res. 45 (5): 1958–1963. PMID 3157441.
  20. ^ Leach, K. L.; James, M. L.; Blumberg, P. M. (1983-07-01). "Characterization of a specific phorbol ester aporeceptor in mouse brain cytosol". Proceedings of the National Academy of Sciences. 80 (14): 4208–4212. Bibcode:1983PNAS...80.4208L. doi:10.1073/pnas.80.14.4208. ISSN 0027-8424. PMC 384006. PMID 6308606.
  21. ^ Leach, K. L.; Grippo, J. F.; Housley, P. R.; Dahmer, M. K.; Salive, M. E.; Pratt, W. B. (1982-01-10). "Characteristics of an endogenous glucocorticoid receptor stabilizing factor". Journal of Biological Chemistry. 257 (1): 381–388. doi:10.1016/S0021-9258(19)68375-4. ISSN 0021-9258. PMID 7053376.
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