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).

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Early life and education

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

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

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

Related Research Articles

<span class="mw-page-title-main">Adenosine triphosphate</span> Energy-carrying molecule in living cells

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Cell biology is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living and functioning of organisms. Cell biology is the study of the structural and functional units of cells. Cell biology encompasses both prokaryotic and eukaryotic cells and has many subtopics which may include the study of cell metabolism, cell communication, cell cycle, biochemistry, and cell composition. The study of cells is performed using several microscopy techniques, cell culture, and cell fractionation. These have allowed for and are currently being used for discoveries and research pertaining to how cells function, ultimately giving insight into understanding larger organisms. Knowing the components of cells and how cells work is fundamental to all biological sciences while also being essential for research in biomedical fields such as cancer, and other diseases. Research in cell biology is interconnected to other fields such as genetics, molecular genetics, molecular biology, medical microbiology, immunology, and cytochemistry.

<span class="mw-page-title-main">Linezolid</span> Antibiotic medication

Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia although it may be used for a variety of other infections including drug-resistant tuberculosis. It is used either by injection into a vein or by mouth.

<span class="mw-page-title-main">Cyclin-dependent kinase</span> Class of enzymes

Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. In fact, yeast cells can proliferate normally when their CDK gene has been replaced with the homologous human gene. CDKs are relatively small proteins, with molecular weights ranging from 34 to 40 kDa, and contain little more than the kinase domain. By definition, a CDK binds a regulatory protein called a cyclin. Without cyclin, CDK has little kinase activity; only the cyclin-CDK complex is an active kinase but its activity can be typically further modulated by phosphorylation and other binding proteins, like p27. CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases. The consensus sequence for the phosphorylation site in the amino acid sequence of a CDK substrate is [S/T*]PX[K/R], where S/T* is the phosphorylated serine or threonine, P is proline, X is any amino acid, K is lysine, and R is arginine.

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide phosphate</span> Chemical compound

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12-<i>O</i>-Tetradecanoylphorbol-13-acetate Chemical compound

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<span class="mw-page-title-main">Cyclin-dependent kinase 4</span> Human protein

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<span class="mw-page-title-main">Cyclin-dependent kinase 6</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.

<span class="mw-page-title-main">Voltage-dependent anion channel</span> Class of porin ion channels in the outer mitochondrial membrane

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<span class="mw-page-title-main">PRKCD</span> Protein-coding gene in the species Homo sapiens

Protein kinase C delta type is an enzyme that in humans is encoded by the PRKCD gene.

<span class="mw-page-title-main">PRKCE</span> Protein-coding gene in the species Homo sapiens

Protein kinase C epsilon type (PKCε) is an enzyme that in humans is encoded by the PRKCE gene. PKCε is an isoform of the large PKC family of protein kinases that play many roles in different tissues. In cardiac muscle cells, PKCε regulates muscle contraction through its actions at sarcomeric proteins, and PKCε modulates cardiac cell metabolism through its actions at mitochondria. PKCε is clinically significant in that it is a central player in cardioprotection against ischemic injury and in the development of cardiac hypertrophy.

<span class="mw-page-title-main">RACGAP1</span> Protein-coding gene in the species Homo sapiens

Rac GTPase-activating protein 1 is an enzyme that in humans is encoded by the RACGAP1 gene.

<span class="mw-page-title-main">PINK1</span> Protein-coding gene in the species Homo sapiens

PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.

<span class="mw-page-title-main">DNM1L</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Cyclin-dependent kinase 3</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 3 is an enzyme that in humans is encoded by the CDK3 gene.

<span class="mw-page-title-main">Cyclin-dependent kinase 10</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 10 is an enzyme that in humans is encoded by the CDK10 gene.

<span class="mw-page-title-main">Cyclin-dependent kinase 5</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Protein synthesis inhibitor</span> Inhibitors of translation

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References

  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. 1 2 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. 1 2 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. 1 2 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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