Nancy Thornberry

Last updated

Nancy Ann Thornberry
Nancy A. Thornberry at SCI-Perkin-Medal-2017-007.jpg
Nancy Thornberry, 2017
NationalityAmerican
Alma mater Muhlenberg College
Awards2011 PhRMA Discoverer’s Award
Scientific career
FieldsMetabolic disorders, Drug discovery
InstitutionsKallyope Inc., Merck Research Laboratories

Nancy A. Thornberry is the founding CEO and current chair, R&D at Kallyope Inc. in New York City. [1] She previously worked with Merck Research Laboratories (MRL), joining the company in 1979 as a biochemist and retiring from the position of senior vice president and franchise head, diabetes and endocrinology in 2013. [2]

Contents

In 1992, Thornberry identified the first caspase, Caspase-1/Interleukin-1 converting enzyme (ICE). [3] In 1999, Thornberry initiated Merck's research into dipeptidyl peptidase-4, leading to the development of FDA-approved treatments for Type 2 diabetes. She has received a number of awards, including the 2011 PhRMA Discoverer’s Award. [2]

Education

Thornberry grew up in South Bend, Indiana. [4] As of 1979, she earned a B.Sc. in Natural Science from Muhlenberg College in Allentown, Pennsylvania. [5] [6]

Career

Thornberry joined Merck Research Laboratories (MRL) in Rahway, New Jersey, as a biochemist in 1979. In 1999 she was appointed the director of enzymology, and in 2001 the director of metabolic disorders, with further promotions in 2007, 2009 and 2011. [7] 

At her retirement from Merck in 2013 Thornberry held the position of senior vice president and franchise head, diabetes and endocrinology. [2]

While an independent consultant to the biotechnology and pharmaceutical industries, Thornberry joined the boards of directors of Intarcia Therapeutics [7] and Abide Therapeutics [8] She subsequently joined the boards of directors of Schrodinger Therapeutics in 2019 [9] and Denali Therapeutics in 2021. [10]

As of November 1, 2015, Thornberry became CEO of Kallyope Inc. in New York City. [2] [11] [12] In October, 2021, Thornberry assumed the post of Chair, R&D while also maintaining her seat on the company’s Board of Directors (succeeded by colleague from Merck, Jay Galeota, who became CEO of Kallyope.) [13] In 2022, she joined the board of the New York Genome Center. [14]

Research

Thornberry's research areas include obesity, diabetes and protease biology. [15] Her work has led to the development of drug candidates including FDA-approved treatments for Type 2 diabetes. [16]

Thornberry was involved in early enzymology research on Lisinopril, an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension. [17] Thornberry also helped to identify Niemann-Pick C1-Like 1 (NPC1L1) as the target of ezetimibe, an inhibitor of cholesterol absorption. [18] [19]

In 1992, her work on proteases led to the identification of the first caspase, caspase-1/Interleukin-1 converting enzyme (ICE). She determined that ICE was the cysteine protease responsible for IL-1β processing in monocytes. [3] [20] Thornberry also developed a novel method for analyzing protease specificities in combinatorial libraries of positional scanning substrates. [21] [8] Her work has led to the broader study of proteases in apoptosis. [22] [23]

External videos
Nuvola apps kaboodle.svg “PhRMA11 Discoverers Award Winner 2011”, PhRMAPress
Nuvola apps kaboodle.svg “Bench to bedside -- discovery of JANUVIA (Sitagliptin)”, Ann Weber & Nancy Thornberry, TEDxNJIT

Beginning in 1999, Thornberry led the biology team for the development of Januvia™ (generic: sitagliptin), a once-a-day oral medication that inhibits the dipeptidyl peptidase-4 (DPP-4) enzyme and improves glucose tolerance to treat Type 2 diabetes. Ann E. Weber led the corresponding chemistry team for the project. [24] [25] [2] The drug was approved by the FDA in October 2006. Janumet™, a drug combining sitagliptin and metformin was also approved, in April 2007. In 2007, the research team at Merck received the Prix Galien USA award for their work on Januvia™. [26] The Januvia™ project was the first project at Merck to be co-led solely by women and the first project co-led solely by women to win the Discoverers Award. [24]

"Discovering an important new medicine is the goal of every person who works in pharmaceutical research. Until it actually happens, though, there is no way to know how absolutely thrilling it is, and how incredibly and deeply satisfying it feels." [27]

At Kallyope Inc., drug discovery focuses on the study of hormonal and neural communication between the gut and the brain to better understand and improve health and nutrition. [2] [28] Kallyope currently has two programs in clinical trials, one targeting metabolic circuits for diabetes and obesity, while the other targets gut barrier function with potential relevance for inflammatory bowel disease and several other diseases. The company also has programs aimed at gastrointestinal, CNS and inflammatory disorders. [29]

Thornberry also serves on the Boards of Directors of Kallyope Inc, Schrodinger Therapeutics, which employs computational biology for the identification of small molecules therapeutics, and Denali Therapeutics, a biotechnology company focused on neurodegeneration. She is also on the board of the New York Genome Center, and a member of the NYC Mayor’s Life Science Advisory Council. [30]

Awards

Related Research Articles

<span class="mw-page-title-main">Protease</span> Enzyme that cleaves other proteins into smaller peptides

A protease is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in numerous biological pathways, including digestion of ingested proteins, protein catabolism, and cell signaling.

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">Cathepsin</span> Family of proteases

Cathepsins are proteases found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave. Most of the members become activated at the low pH found in lysosomes. Thus, the activity of this family lies almost entirely within those organelles. There are, however, exceptions such as cathepsin K, which works extracellularly after secretion by osteoclasts in bone resorption. Cathepsins have a vital role in mammalian cellular turnover.

<span class="mw-page-title-main">Death effector domain</span> InterPro Domain

The death-effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates a variety of cellular signalling pathways. The DED domain is found in inactive procaspases and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein (FADD). FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex (DISC). This recruitment is mediated by a homotypic interaction between the procaspase DED and a second DED that is death effector domain in an adaptor protein that is directly associated with activated TNF receptors. Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis. Structurally the DED domain are a subclass of protein motif known as the death fold and contains 6 alpha helices, that closely resemble the structure of the Death domain (DD).

Benjamin Franklin Cravatt III is a professor in the Department of Chemistry at The Scripps Research Institute in La Jolla, California. Considered a co-inventor of activity-based proteomics and a substantial contributor to research on the endocannabinoid system, he is a prominent figure in the nascent field of chemical biology. Cravatt was elected to the National Academy of Sciences in 2014, and the American Academy of Arts and Sciences in 2016. He is Gilula Chair of Chemical Biology, a Cope Scholar, and a Searle Scholar.

<span class="mw-page-title-main">Sitagliptin</span> Diabetes medication

Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea. It is taken by mouth. It is also available in the fixed-dose combination medication sitagliptin/metformin.

<span class="mw-page-title-main">Caspase 1</span> Protein-coding gene in the species Homo sapiens

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

<span class="mw-page-title-main">Caspase-9</span> Protein-coding gene in the species Homo sapiens

Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

Caspase 4 is an enzyme that proteolytically cleaves other proteins at an aspartic acid residue (LEVD-), and belongs to a family of cysteine proteases called caspases. The function of caspase 4 is not fully known, but it is believed to be an inflammatory caspase, along with caspase 1, caspase 5, with a role in the immune system.

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

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

Xiaodong Wang is a Chinese-American biochemist best known for his work with apoptosis, one of the ways through which cells kill themselves.

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

Caspase-6 is an enzyme that in humans is encoded by the CASP6 gene. CASP6 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. Caspase-6 has known functions in apoptosis, early immune response and neurodegeneration in Huntington's and Alzheimer's disease.

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

Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.

Dipeptidyl peptidase-4 inhibitors are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4). They are used in the treatment of type 2 diabetes mellitus. Inhibition of the DPP-4 enzyme prolongs and enhances the activity of incretins that play an important role in insulin secretion and blood glucose control regulation. Type 2 diabetes mellitus is a chronic metabolic disease that results from inability of the β-cells in the pancreas to secrete sufficient amounts of insulin to meet the body's needs. Insulin resistance and increased hepatic glucose production can also play a role by increasing the body's demand for insulin. Current treatments, other than insulin supplementation, are sometimes not sufficient to achieve control and may cause undesirable side effects, such as weight gain and hypoglycemia. In recent years, new drugs have been developed, based on continuing research into the mechanism of insulin production and regulation of the metabolism of sugar in the body. The enzyme DPP-4 has been found to play a significant role.

Caspase-2 is an enzyme. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Early 35 kDa protein</span> Anti-apoptotic viral protein

The Early 35 kDa protein, or P35 in short, is a baculoviral protein that inhibits apoptosis in the cells infected by the virus. Although baculoviruses infect only invertebrates in nature, ectopic expression of P35 in vertebrate animals and cells also results in inhibition of apoptosis, thus indicating a universal mechanism. P35 has been shown to be a caspase inhibitor with a very wide spectrum of activity both in regard to inhibited caspase types and to species in which the mechanism is conserved.

<span class="mw-page-title-main">Emma Parmee</span> British chemist

Emma Parmee is a British chemist and research scientist who is a co-inventor of numerous drug patents. She was one of the leading researchers in the development of sitagliptin and was awarded a Thomas Alva Edison Patent Award in 2007 and the Society of Chemical Industry's Gordon E Moore Medal in 2009 for her contributions.

<span class="mw-page-title-main">Ann E. Weber</span>

Ann E. Weber is the senior vice president for drug discovery at Kallyope Inc. in New York City. She previously worked with Merck Research Laboratories (MRL), joining the company in 1987 and retiring from the position of vice president for lead optimization chemistry in 2015. She has helped develop more than 40 drug candidates including FDA-approved treatments for Type 2 diabetes. She has received a number of awards, including the Perkin Medal (2017) and has been inducted into the ACS Division of Medicinal Chemistry’s MEDI Hall of Fame.

<span class="mw-page-title-main">Papain-like protease</span>

Papain-like proteases are a large protein family of cysteine protease enzymes that share structural and enzymatic properties with the group's namesake member, papain. They are found in all domains of life. In animals, the group is often known as cysteine cathepsins or, in older literature, lysosomal peptidases. In the MEROPS protease enzyme classification system, papain-like proteases form Clan CA. Papain-like proteases share a common catalytic dyad active site featuring a cysteine amino acid residue that acts as a nucleophile.

References

  1. ↑ "New York City arrives as a home for the life sciences". Chemical & Engineering News . Retrieved 3 October 2022.
  2. 1 2 3 4 5 6 Wolfe, Josh (28 June 2016). "Harnessing The Gut-Brain Axis". Forbes. Retrieved 9 October 2017.
  3. 1 2 Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J (April 1992). "A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes". Nature. 356 (6372): 768–74. Bibcode:1992Natur.356..768T. doi:10.1038/356768a0. PMID   1574116. S2CID   4310923.
  4. ↑ "Discoverer's Award 2011" (PDF). PhRMA. Retrieved 16 October 2017.
  5. ↑ "Class of 1979". Muhlenberg College. Retrieved 13 October 2017.
  6. ↑ Ciarla: An informal history of Muhlenberg College 1978-1979. Allentown, Pennsylvania: Muhlenberg College. 1979. p. 220. Retrieved 13 October 2017.
  7. 1 2 "Intarcia Therapeutics Appoints Nancy Thornberry to Board of Directors". Intarcia Therapeutics. 2 December 2013. Retrieved 13 October 2017.
  8. 1 2 3 "Abide Therapeutics Appoints Nancy Thornberry to Board of Directors". Abide Therapeutics. 29 July 2014.
  9. ↑ "Schrödinger Appoints Drug Discovery Veteran Nancy Thornberry to Board of Directors". Business Wire. Retrieved 24 September 2019.
  10. ↑ "Denali Therapeutics Announces Appointment of Nancy Thornberry to Board of Directors". Yahoo Finance. Retrieved 11 January 2021.,
  11. ↑ Khamsi, Roxanne. "Metabolism in Mind: New Insights into the "Gut–Brain Axis" Spur Commercial Efforts to Target It What if controlling the appetite were as easy as flipping a switch?". Scientific American. Retrieved 16 October 2017.
  12. ↑ Swetlitz, Ike (10 December 2015). "This biotech startup wants to access your brain through the microbes in your gut". Business Insider. Retrieved 16 October 2017.
  13. ↑ "Kallyope Announces CEO Transition as Company Advances to its Next Stage of Growth". biospace news. Retrieved 5 August 2021.
  14. ↑ "Nancy Thornberry". New York Genome Center. Retrieved 15 October 2023.
  15. ↑ Turk, Boris; Turk, Dušan; Turk, Vito (2012). "Protease signalling: the cutting edge". EMBO Journal. 31 (7): 1630–1643. doi:10.1038/emboj.2012.42. PMC   3321211 . PMID   22367392.
  16. ↑ "Kallyope Receives $8.2 Million Grant from Gates Foundation". Citybiz. Retrieved 11 May 2023.
  17. ↑ Bull, HG; Thornberry, NA; Cordes, EH (10 March 1985). "Purification of angiotensin-converting enzyme from rabbit lung and human plasma by affinity chromatography". The Journal of Biological Chemistry. 260 (5): 2963–72. doi: 10.1016/S0021-9258(18)89460-1 . PMID   2982846.
  18. ↑ Garcia-Calvo, M.; Lisnock, J.; Bull, H. G.; et al. (2005). "The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1)". Proceedings of the National Academy of Sciences. 102 (23): 8132–8137. Bibcode:2005PNAS..102.8132G. doi: 10.1073/pnas.0500269102 . PMC   1149415 . PMID   15928087.
  19. ↑ Huff, M. W.; Pollex, R. L.; Hegele, R. A. (1 November 2006). "NPC1L1: Evolution From Pharmacological Target to Physiological Sterol Transporter". Arteriosclerosis, Thrombosis, and Vascular Biology. 26 (11): 2433–2438. doi: 10.1161/01.ATV.0000245791.53245.ee . PMID   16973966.
  20. ↑ Thornberry, Nancy A.; Molineaux, Susan M. (1995). "Interleukin-1P converting enzyme: A novel cysteine protease required for IL-lP production and implicated in programmed cell death". Protein Science. 4 (4): 3–12. doi:10.1002/pro.5560040102. PMC   2142972 . PMID   7773174.
  21. ↑ Thornberry, Nancy A.; Rano, Thomas A.; Peterson, Erin P.; Rasper, Dita M.; Timkey, Tracy; Garcia-Calvo, Margarita; Houtzager, Vicky M.; Nordstrom, Penny A.; Roy, Sophie; Vaillancourt, John P.; Chapman, Kevin T.; Nicholson, Donald W. (18 July 1997). "A Combinatorial Approach Defines Specificities of Members of the Caspase Family and Granzyme B". Journal of Biological Chemistry. 272 (29): 17907–17911. doi: 10.1074/jbc.272.29.17907 . PMID   9218414.
  22. ↑ Thornberry, N. A (1 January 1997). "The caspase family of cysteine proteases". British Medical Bulletin. 53 (3): 478–490. doi: 10.1093/oxfordjournals.bmb.a011625 . PMID   9374032 . Retrieved 16 October 2017.
  23. ↑ Schwartz, Lawrence M.; Ashwell, Jonathan, eds. (2001). Apoptosis. Methods in Cell Biology. Vol. 66. San Diego, California: Academic Press. p. 15. ISBN   978-0125441650 . Retrieved 16 October 2017.
  24. 1 2 3 "Women Scientists Honored For New Diabetes Oral Medication". PhRMA. 14 April 2011. Archived from the original on 17 May 2018. Retrieved 9 October 2017.
  25. ↑ Cordes, Eugene H. (2014). Hallelujah moments : tales of drug discovery. Oxford, UK: Oxford University Press. pp. 207–. ISBN   9780199337149 . Retrieved 9 October 2017.
  26. ↑ Stowe, Gene (10 April 2008). "Distinguished alumna lecture is like a "mini course in medicinal chemistry"". University of Notre Dame News. Retrieved 9 October 2017.
  27. ↑ "Skill, Vision and Effort Rewarded". Merck. Retrieved 13 October 2017.
  28. ↑ Carroll, John (10 December 2015). "In a win for NYC, gut-brain biotech Kallyope launches with $44M". Fierce Biotech. Retrieved 16 October 2017.
  29. ↑ "Kallyope to expand its metabolic disorder programme globally". Clinical Trials Arena. Retrieved 25 October 2023.
  30. ↑ "Vertex taps longtime commercial lead to fill two-year COO vacancy; Nancy Thornberry set for different role at Kallyope with an old friend from Merck waiting in the wings". Endpoints News. Retrieved 6 August 2021.
  31. ↑ "Women in STEM honored at LSC annual luncheon". LSC News. Liberty Science Center. 11 December 2013.
  32. ↑ "Industry Researchers Honored with Coveted Thomas Alva Edison Patent Award". HealthCare Institute of New Jersey. 16 November 2011. Retrieved 16 October 2017.
  33. ↑ "New Heroes of Chemistry invented medicines that help millions of people". American Chemical Society. Retrieved 19 August 2010.
  34. ↑ "Heroes of Chemistry Award". American Chemical Society. Retrieved 9 October 2017.
  35. ↑ Ainsworth, Susan J. (11 October 2010). "ACS Honors Heroes Of Chemistry 2010". Chemical & Engineering News. 88 (41): 43. doi:10.1021/cen-v088n041.p043 . Retrieved 13 October 2017.
  36. ↑ Prohaska, Stacey (2012). "Victory at Last: The Muhlenberg Grad Behind an Important Diabetes Treatment" (PDF). Muhlenberg, The Magazine. No. Winter. Retrieved 16 October 2017.
  37. ↑ "Discovery of the Decade" (PDF). The Prix Galien USA Awards. Retrieved 9 October 2017.
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