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1. A deep learning approach predicting the activity of COVID-19 therapeutics and vaccines against emerging variants.

Author

Matson, Robert P., Comba, Isin Y., Silvert, Eli, Niesen, Michiel J. M., Murugadoss, Karthik, Patwardhan, Dhruti, Suratekar, Rohit, Goel, Elizabeth-Grace, Poelaert, Brittany J., Wan, Kanny K., Brimacombe, Kyle R., Venkatakrishnan, AJ, and Soundararajan, Venky

Abstract

Understanding which viral variants evade neutralization is crucial for improving antibody-based treatments, especially with rapidly evolving viruses like SARS-CoV-2. Yet, conventional assays are labor intensive and cannot capture the full spectrum of variants. We present a deep learning approach to predict changes in neutralizing antibody activity of COVID-19 therapeutics and vaccine-elicited sera/plasma against emerging viral variants. Our approach leverages data of 67,885 unique SARS-CoV-2 Spike sequences and 7,069 in vitro assays. The resulting model accurately predicted fold changes in neutralizing activity (R2 = 0.77) for a test set (N = 980) of data collected up to eight months after the training data. Next, the model was used to predict changes in activity of current therapeutic and vaccine-induced antibodies against emerging SARS-CoV-2 lineages. Consistent with other work, we found significantly reduced activity against newer XBB descendants, notably EG.5, FL.1.5.1, and XBB.1.16; primarily attributed to the F456L spike mutation. [ABSTRACT FROM AUTHOR]

Published
2024
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2. Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space.

Author

Kearney, Sara E, Zahoránszky-Kőhalmi, Gergely, Brimacombe, Kyle R, Henderson, Mark J, Lynch, Caitlin, Zhao, Tongan, Wan, Kanny K, Itkin, Zina, Dillon, Christopher, Shen, Min, Cheff, Dorian M, Lee, Tobie D, Bougie, Danielle, Cheng, Ken, Coussens, Nathan P, Dorjsuren, Dorjbal, Eastman, Richard T, Huang, Ruili, Iannotti, Michael J, Karavadhi, Surendra, Klumpp-Thomas, Carleen, Roth, Jacob S, Sakamuru, Srilatha, Sun, Wei, Titus, Steven A, Yasgar, Adam, Zhang, Ya-Qin, Zhao, Jinghua, Andrade, Rodrigo B, Brown, M Kevin, Burns, Noah Z, Cha, Jin K, Mevers, Emily E, Clardy, Jon, Clement, Jason A, Crooks, Peter A, Cuny, Gregory D, Ganor, Jake, Moreno, Jesus, Morrill, Lucas A, Picazo, Elias, Susick, Robert B, Garg, Neil K, Goess, Brian C, Grossman, Robert B, Hughes, Chambers C, Johnston, Jeffrey N, Joullie, Madeleine M, Kinghorn, A Douglas, Kingston, David GI, Krische, Michael J, Kwon, Ohyun, Maimone, Thomas J, Majumdar, Susruta, Maloney, Katherine N, Mohamed, Enas, Murphy, Brian T, Nagorny, Pavel, Olson, David E, Overman, Larry E, Brown, Lauren E, Snyder, John K, Porco, John A, Rivas, Fatima, Ross, Samir A, Sarpong, Richmond, Sharma, Indrajeet, Shaw, Jared T, Xu, Zhengren, Shen, Ben, Shi, Wei, Stephenson, Corey RJ, Verano, Alyssa L, Tan, Derek S, Tang, Yi, Taylor, Richard E, Thomson, Regan J, Vosburg, David A, Wu, Jimmy, Wuest, William M, Zakarian, Armen, Zhang, Yufeng, Ren, Tianjing, Zuo, Zhong, Inglese, James, Michael, Sam, Simeonov, Anton, Zheng, Wei, Shinn, Paul, Jadhav, Ajit, Boxer, Matthew B, Hall, Matthew D, Xia, Menghang, Guha, Rajarshi, and Rohde, Jason M

Subjects
Chemical Sciences
Abstract

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (-)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.

Published
2018

5. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Author

Anastasiou, Dimitrios, Yu, Yimin, Israelsen, William J, Jiang, Jian-Kang, Boxer, Matthew B, Hong, Bum Soo, Tempel, Wolfram, Dimov, Svetoslav, Shen, Min, Jha, Abhishek, Yang, Hua, Mattaini, Katherine R, Metallo, Christian M, Fiske, Brian P, Courtney, Kevin D, Malstrom, Scott, Khan, Tahsin M, Kung, Charles, Skoumbourdis, Amanda P, Veith, Henrike, Southall, Noel, Walsh, Martin J, Brimacombe, Kyle R, Leister, William, Lunt, Sophia Y, Johnson, Zachary R, Yen, Katharine E, Kunii, Kaiko, Davidson, Shawn M, Christofk, Heather R, Austin, Christopher P, Inglese, James, Harris, Marian H, Asara, John M, Stephanopoulos, Gregory, Salituro, Francesco G, Jin, Shengfang, Dang, Lenny, Auld, Douglas S, Park, Hee-Won, Cantley, Lewis C, Thomas, Craig J, and Vander Heiden, Matthew G

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, Animals, Biopolymers, Blotting, Western, Cell Proliferation, Cell Transformation, Neoplastic, Enzyme Activators, Humans, Mice, Neoplasms, Pyruvate Kinase, Medicinal and Biomolecular Chemistry, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism.

Published
2012

6. Report of the Assay Guidance Workshop on 3-Dimensional Tissue Models for Antiviral Drug Development

Author

Jordan, Robert, primary, Ford-Scheimer, Stephanie L, additional, Alarcon, Rodolfo M, additional, Atala, Anthony, additional, Borenstein, Jeffrey T, additional, Brimacombe, Kyle R, additional, Cherry, Sara, additional, Clevers, Hans, additional, Davis, Mindy I, additional, Funnell, Simon G P, additional, Gehrke, Lee, additional, Griffith, Linda G, additional, Grossman, Abigail C, additional, Hartung, Thomas, additional, Ingber, Donald E, additional, Kleinstreuer, Nicole C, additional, Kuo, Calvin J, additional, Lee, Emily M, additional, Mummery, Christine L, additional, Pickett, Thames E, additional, Ramani, Sasirekha, additional, Rosado-Olivieri, Edwin A, additional, Struble, Evi B, additional, Wan, Zhengpeng, additional, Williams, Mark S, additional, Hall, Matthew D, additional, Ferrer, Marc, additional, and Markossian, Sarine, additional

Published
2023
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7. Supplementary Figure S6 from Quantitative High-Throughput Screening Using an Organotypic Model Identifies Compounds that Inhibit Ovarian Cancer Metastasis

Author

Kenny, Hilary A., primary, Lal-Nag, Madhu, primary, Shen, Min, primary, Kara, Betul, primary, Nahotko, Dominik A., primary, Wroblewski, Kristen, primary, Fazal, Sarah, primary, Chen, Siquan, primary, Chiang, Chun-Yi, primary, Chen, Yen-Ju, primary, Brimacombe, Kyle R., primary, Marugan, Juan, primary, Ferrer, Marc, primary, and Lengyel, Ernst, primary

Published
2023
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8. Data from Quantitative High-Throughput Screening Using an Organotypic Model Identifies Compounds that Inhibit Ovarian Cancer Metastasis

Author

Kenny, Hilary A., primary, Lal-Nag, Madhu, primary, Shen, Min, primary, Kara, Betul, primary, Nahotko, Dominik A., primary, Wroblewski, Kristen, primary, Fazal, Sarah, primary, Chen, Siquan, primary, Chiang, Chun-Yi, primary, Chen, Yen-Ju, primary, Brimacombe, Kyle R., primary, Marugan, Juan, primary, Ferrer, Marc, primary, and Lengyel, Ernst, primary

Published
2023
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9. Supplementary Table S1 from Quantitative High-Throughput Screening Using an Organotypic Model Identifies Compounds that Inhibit Ovarian Cancer Metastasis

Author

Kenny, Hilary A., primary, Lal-Nag, Madhu, primary, Shen, Min, primary, Kara, Betul, primary, Nahotko, Dominik A., primary, Wroblewski, Kristen, primary, Fazal, Sarah, primary, Chen, Siquan, primary, Chiang, Chun-Yi, primary, Chen, Yen-Ju, primary, Brimacombe, Kyle R., primary, Marugan, Juan, primary, Ferrer, Marc, primary, and Lengyel, Ernst, primary

Published
2023
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10. Supplementary Methods from Quantitative High-Throughput Screening Using an Organotypic Model Identifies Compounds that Inhibit Ovarian Cancer Metastasis

Author

Kenny, Hilary A., primary, Lal-Nag, Madhu, primary, Shen, Min, primary, Kara, Betul, primary, Nahotko, Dominik A., primary, Wroblewski, Kristen, primary, Fazal, Sarah, primary, Chen, Siquan, primary, Chiang, Chun-Yi, primary, Chen, Yen-Ju, primary, Brimacombe, Kyle R., primary, Marugan, Juan, primary, Ferrer, Marc, primary, and Lengyel, Ernst, primary

Published
2023
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11. Report of the Assay Guidance Workshop on 3-Dimensional Tissue Models for Antiviral Drug Development

Author

Jordan, Robert, Ford-Scheimer, Stephanie L, Alarcon, Rodolfo M, Atala, Anthony, Borenstein, Jeffrey T, Brimacombe, Kyle R, Cherry, Sara, Clevers, Hans, Davis, Mindy I, Funnell, Simon G P, Gehrke, Lee, Griffith, Linda G, Grossman, Abigail C, Hartung, Thomas, Ingber, Donald E, Kleinstreuer, Nicole C, Kuo, Calvin J, Lee, Emily M, Mummery, Christine L, Pickett, Thames E, Ramani, Sasirekha, Rosado-Olivieri, Edwin A, Struble, Evi B, Wan, Zhengpeng, Williams, Mark S, Hall, Matthew D, Ferrer, Marc, Markossian, Sarine, Jordan, Robert, Ford-Scheimer, Stephanie L, Alarcon, Rodolfo M, Atala, Anthony, Borenstein, Jeffrey T, Brimacombe, Kyle R, Cherry, Sara, Clevers, Hans, Davis, Mindy I, Funnell, Simon G P, Gehrke, Lee, Griffith, Linda G, Grossman, Abigail C, Hartung, Thomas, Ingber, Donald E, Kleinstreuer, Nicole C, Kuo, Calvin J, Lee, Emily M, Mummery, Christine L, Pickett, Thames E, Ramani, Sasirekha, Rosado-Olivieri, Edwin A, Struble, Evi B, Wan, Zhengpeng, Williams, Mark S, Hall, Matthew D, Ferrer, Marc, and Markossian, Sarine

Abstract

The National Center for Advancing Translational Sciences (NCATS) Assay Guidance Manual (AGM) Workshop on 3D Tissue Models for Antiviral Drug Development, held virtually on 7-8 June 2022, provided comprehensive coverage of critical concepts intended to help scientists establish robust, reproducible, and scalable 3D tissue models to study viruses with pandemic potential. This workshop was organized by NCATS, the National Institute of Allergy and Infectious Diseases, and the Bill and Melinda Gates Foundation. During the workshop, scientific experts from academia, industry, and government provided an overview of 3D tissue models' utility and limitations, use of existing 3D tissue models for antiviral drug development, practical advice, best practices, and case studies about the application of available 3D tissue models to infectious disease modeling. This report includes a summary of each workshop session as well as a discussion of perspectives and challenges related to the use of 3D tissues in antiviral drug discovery.

Published
2023

12. Report of the Assay Guidance Workshop on 3-Dimensional Tissue Models for Antiviral Drug Development

Author

CMM, Cancer, Hubrecht Institute with UMC, Jordan, Robert, Ford-Scheimer, Stephanie L., Alarcon, Rodolfo M., Atala, Anthony, Borenstein, Jeffrey T., Brimacombe, Kyle R., Cherry, Sara, Clevers, Hans, Davis, Mindy I., Funnell, Simon G.P., Gehrke, Lee, Griffith, Linda G., Grossman, Abigail C., Hartung, Thomas, Ingber, Donald E., Kleinstreuer, Nicole C., Kuo, Calvin J., Lee, Emily M., Mummery, Christine L., Pickett, Thames E., Ramani, Sasirekha, Rosado-Olivieri, Edwin A., Struble, Evi B., Wan, Zhengpeng, Williams, Mark S., Hall, Matthew D., Ferrer, Marc, Markossian, Sarine, CMM, Cancer, Hubrecht Institute with UMC, Jordan, Robert, Ford-Scheimer, Stephanie L., Alarcon, Rodolfo M., Atala, Anthony, Borenstein, Jeffrey T., Brimacombe, Kyle R., Cherry, Sara, Clevers, Hans, Davis, Mindy I., Funnell, Simon G.P., Gehrke, Lee, Griffith, Linda G., Grossman, Abigail C., Hartung, Thomas, Ingber, Donald E., Kleinstreuer, Nicole C., Kuo, Calvin J., Lee, Emily M., Mummery, Christine L., Pickett, Thames E., Ramani, Sasirekha, Rosado-Olivieri, Edwin A., Struble, Evi B., Wan, Zhengpeng, Williams, Mark S., Hall, Matthew D., Ferrer, Marc, and Markossian, Sarine

Published
2023

13. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo

Author

Najm, Fadi J., Madhavan, Mayur, Zaremba, Anita, Shick, Elizabeth, Karl, Robert T., Factor, Daniel C., Miller, Tyler E., Nevin, Zachary S., Kantor, Christopher, Sargent, Alex, Quick, Kevin L., Schlatzer, Daniela M., Tang, Hong, Papoian, Ruben, Brimacombe, Kyle R., Shen, Min, Boxer, Matthew B., Jadhav, Ajit, Robinson, Andrew P., Podojil, Joseph R., Miller, Stephen D., Miller, Robert H., and Tesar, Paul J.

Subjects
Medical research, Medicine, Experimental, Multiple sclerosis -- Research, Stem cells -- Physiological aspects, Myelination -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes (1). These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention (2). To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells (3-5). Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients., As repair of damaged myelin may provide therapeutic benefit in multiple sclerosis (MS) and other demyelinating disorders (6-12), we set out to identify drugs that could be re-purposed as remyelinating [...]

Published
2015

15. Optimization of ether and aniline based inhibitors of lactate dehydrogenase

Author

Christov, Plamen P., Kim, Kwangho, Jana, Somnath, Romaine, Ian M., Rai, Ganesha, Mott, Bryan T., Allweil, Alexander A., Lamers, Alexander, Brimacombe, Kyle R., Urban, Daniel J., Lee, Tobie D., Hu, Xin, Lukacs, Christine M., Davies, Douglas R., Jadhav, Ajit, Hall, Matthew D., Green, Neal, Moore, William J., Stott, Gordon M., Flint, Andrew J., Maloney, David J., Sulikowski, Gary A., and Waterson, Alex G.

Published
2021
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17. Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

Author

Hall, Matthew D, primary, Anderson, James M, additional, Anderson, Annaliesa, additional, Baker, David, additional, Bradner, Jay, additional, Brimacombe, Kyle R, additional, Campbell, Elizabeth A, additional, Corbett, Kizzmekia S, additional, Carter, Kara, additional, Cherry, Sara, additional, Chiang, Lillian, additional, Cihlar, Tomas, additional, de Wit, Emmie, additional, Denison, Mark, additional, Disney, Matthew, additional, Fletcher, Courtney V, additional, Ford-Scheimer, Stephanie L, additional, Götte, Matthias, additional, Grossman, Abigail C, additional, Hayden, Frederick G, additional, Hazuda, Daria J, additional, Lanteri, Charlotte A, additional, Marston, Hilary, additional, Mesecar, Andrew D, additional, Moore, Stephanie, additional, Nwankwo, Jennifer O, additional, O’Rear, Jules, additional, Painter, George, additional, Singh Saikatendu, Kumar, additional, Schiffer, Celia A, additional, Sheahan, Timothy P, additional, Shi, Pei-Yong, additional, Smyth, Hugh D, additional, Sofia, Michael J, additional, Weetall, Marla, additional, Weller, Sandra K, additional, Whitley, Richard, additional, Fauci, Anthony S, additional, Austin, Christopher P, additional, Collins, Francis S, additional, Conley, Anthony J, additional, and Davis, Mindy I, additional

Published
2021
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18. Discovery and Optimization of 2H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer

Author

Rohde, Jason M., primary, Karavadhi, Surendra, additional, Pragani, Rajan, additional, Liu, Li, additional, Fang, Yuhong, additional, Zhang, Weihe, additional, McIver, Andrew, additional, Zheng, Hongchao, additional, Liu, Qingyang, additional, Davis, Mindy I., additional, Urban, Daniel J., additional, Lee, Tobie D., additional, Cheff, Dorian M., additional, Hollingshead, Melinda, additional, Henderson, Mark J., additional, Martinez, Natalia J., additional, Brimacombe, Kyle R., additional, Yasgar, Adam, additional, Zhao, Wei, additional, Klumpp-Thomas, Carleen, additional, Michael, Sam, additional, Covey, Joseph, additional, Moore, William J., additional, Stott, Gordon M., additional, Li, Zhuyin, additional, Simeonov, Anton, additional, Jadhav, Ajit, additional, Frye, Stephen, additional, Hall, Matthew D., additional, Shen, Min, additional, Wang, Xiaodong, additional, Patnaik, Samarjit, additional, and Boxer, Matthew B., additional

Published
2021
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19. Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors

Author

Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Rohde, Jason M., Brimacombe, Kyle R., Liu, Li, Pacold, Michael Edward, Yasgar, Adam, Cheff, Dorian M., Lee, Tobie D., Rai, Ganesha, Baljinnyam, Bolormaa, Li, Zhuyin, Simeonov, Anton, Hall, Matthew D., Shen, Min, Sabatini, David, Boxer, Matthew B., Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Rohde, Jason M., Brimacombe, Kyle R., Liu, Li, Pacold, Michael Edward, Yasgar, Adam, Cheff, Dorian M., Lee, Tobie D., Rai, Ganesha, Baljinnyam, Bolormaa, Li, Zhuyin, Simeonov, Anton, Hall, Matthew D., Shen, Min, Sabatini, David, and Boxer, Matthew B.

Abstract

Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To discover inhibitors of PHGDH, a coupled biochemical assay was developed and optimized to enable high-throughput screening for inhibitors of human PHGDH. Feedback inhibition was minimized by coupling PHGDH activity to two downstream enzymes (PSAT1 and PSPH), providing a marked improvement in enzymatic turnover. Further coupling of NADH to a diaphorase/resazurin system enabled a red-shifted detection readout, minimizing interference due to compound autofluorescence. With this protocol, over 400,000 small molecules were screened for PHGDH inhibition, and following hit validation and triage work, a piperazine-1-thiourea was identified. Following rounds of medicinal chemistry and SAR exploration, two probes (NCT-502 and NCT-503) were identified. These molecules demonstrated improved target activity and encouraging ADME properties, enabling in vitro assessment of the biological importance of PHGDH, and its role in the fate of serine in PHGDH-dependent cancer cells. This manuscript reports the assay development and medicinal chemistry leading to the development of NCT-502 and -503 reported in Pacold et al. (2016). Keywords: PHGDH; inhibitor; serine, National Institutes of Health (U.S.) (Grant U54MH084681), National Institutes of Health (U.S.) (R37 AI047389), National Institutes of Health (U.S.) (R01 CA103866), National Institutes of Health (U.S.) (R01 CA129105), National Institutes of Health (U.S.) (R37 AI047389), National Institutes of Health (U.S.) (K22 CA212059), Mary Kay Foundation (017-32), V foundation (V2017-004)

Published
2020

20. Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties

Author

Rai, Ganesha, primary, Urban, Daniel J., additional, Mott, Bryan T., additional, Hu, Xin, additional, Yang, Shyh-Ming, additional, Benavides, Gloria A., additional, Johnson, Michelle S., additional, Squadrito, Giuseppe L., additional, Brimacombe, Kyle R., additional, Lee, Tobie D., additional, Cheff, Dorian M., additional, Zhu, Hu, additional, Henderson, Mark J., additional, Pohida, Katherine, additional, Sulikowski, Gary A., additional, Dranow, David M., additional, Kabir, Md, additional, Shah, Pranav, additional, Padilha, Elias, additional, Tao, Dingyin, additional, Fang, Yuhong, additional, Christov, Plamen P., additional, Kim, Kwangho, additional, Jana, Somnath, additional, Muttil, Pavan, additional, Anderson, Tamara, additional, Kunda, Nitesh K., additional, Hathaway, Helen J., additional, Kusewitt, Donna F., additional, Oshima, Nobu, additional, Cherukuri, Murali, additional, Davies, Douglas R., additional, Norenberg, Jeffrey P., additional, Sklar, Larry A., additional, Moore, William J., additional, Dang, Chi V., additional, Stott, Gordon M., additional, Neckers, Leonard, additional, Flint, Andrew J., additional, Darley-Usmar, Victor M., additional, Simeonov, Anton, additional, Waterson, Alex G., additional, Jadhav, Ajit, additional, Hall, Matthew D., additional, and Maloney, David J., additional

Published
2020
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22. An OpenData portal to share COVID-19 drug repurposing data in real time

Author

Brimacombe, Kyle R., primary, Zhao, Tongan, additional, Eastman, Richard T., additional, Hu, Xin, additional, Wang, Ke, additional, Backus, Mark, additional, Baljinnyam, Bolormaa, additional, Chen, Catherine Z., additional, Chen, Lu, additional, Eicher, Tara, additional, Ferrer, Marc, additional, Fu, Ying, additional, Gorshkov, Kirill, additional, Guo, Hui, additional, Hanson, Quinlin M., additional, Itkin, Zina, additional, Kales, Stephen C., additional, Klumpp-Thomas, Carleen, additional, Lee, Emily M., additional, Michael, Sam, additional, Mierzwa, Tim, additional, Patt, Andrew, additional, Pradhan, Manisha, additional, Renn, Alex, additional, Shinn, Paul, additional, Shrimp, Jonathan H., additional, Viraktamath, Amit, additional, Wilson, Kelli M., additional, Xu, Miao, additional, Zakharov, Alexey V., additional, Zhu, Wei, additional, Zheng, Wei, additional, Simeonov, Anton, additional, Mathé, Ewy A., additional, Lo, Donald C., additional, Hall, Matthew D., additional, and Shen, Min, additional

Published
2020
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25. Correction: Inhibition of glutathione peroxidase mediates the collateral sensitivity of multidrug-resistant cells to tiopronin.

Author

Hall, Matthew D., primary, Marshall, Travis S., additional, Kwit, Alexandra D.T., additional, Miller Jenkins, Lisa M., additional, Dulcey, Andrés E., additional, Madigan, James P., additional, Pluchino, Kristen M., additional, Goldsborough, Andrew S., additional, Brimacombe, Kyle R., additional, Griffiths, Gary L., additional, and Gottesman, Michael M., additional

Published
2020
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27. Quantitative High-Throughput Screening Using an Organotypic Model Identifies Compounds that Inhibit Ovarian Cancer Metastasis

Author

Kenny, Hilary A., primary, Lal-Nag, Madhu, additional, Shen, Min, additional, Kara, Betul, additional, Nahotko, Dominik A., additional, Wroblewski, Kristen, additional, Fazal, Sarah, additional, Chen, Siquan, additional, Chiang, Chun-Yi, additional, Chen, Yen-Ju, additional, Brimacombe, Kyle R., additional, Marugan, Juan, additional, Ferrer, Marc, additional, and Lengyel, Ernst, additional

Published
2020
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28. A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein

Author

Lee, Tobie D., primary, Lee, Olivia W., additional, Brimacombe, Kyle R., additional, Chen, Lu, additional, Guha, Rajarshi, additional, Lusvarghi, Sabrina, additional, Tebase, Bethilehem G., additional, Klumpp-Thomas, Carleen, additional, Robey, Robert W., additional, Ambudkar, Suresh V., additional, Shen, Min, additional, Gottesman, Michael M., additional, and Hall, Matthew D., additional

Published
2019
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29. A High-Throughput Screen of a Library of Therapeutics Identifies Substrates of P-glycoprotein

Author

Lee, Tobie D., primary, Lee, Olivia W., additional, Brimacombe, Kyle R., additional, Chen, Lu, additional, Guha, Rajarshi, additional, Lusvarghi, Sabrina, additional, Tebase, Bethilehem G., additional, Klumpp-Thomas, Carleen, additional, Robey, Robert W., additional, Ambudkar, Suresh V., additional, Shen, Min, additional, Gottesman, Michael M., additional, and Hall, Matthew D., additional

Published
2019
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30. Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

Author

Sharma Kamal, Wilson Colin M, Auh Sungyoung, Sousa Alioscka A, Fung Steve H, Brimacombe Kyle R, Wu Haitao, Kanevsky Ariel S, Sarin Hemant, Aronova Maria A, Leapman Richard D, Griffiths Gary L, and Hall Matthew D

Subjects
Medicine
Abstract

Abstract Background Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells. Methods Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured in vivo with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed ex vivo with fluorescence imaging. Results We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells. Conclusion The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.

Published
2008
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31. Canvass: A Crowd-Sourced, Natural Product Screening Library for Exploring Biological Space

Author

Kearney, Sara E., primary, Zahoránszky-Kőhalmi, Gergely, primary, Brimacombe, Kyle R., primary, Henderson, Mark J., primary, Lynch, Caitlin, primary, Zhao, Tongan, primary, Wan, Kanny K., primary, Itkin, Zina, primary, Dillon, Christopher, primary, Shen, Min, primary, Cheff, Dorian M., primary, Lee, Tobie D., primary, Bougie, Danielle, primary, Cheng, Ken, primary, Coussens, Nathan, primary, Dorjsuren, Dorjbal, primary, Eastman, Richard T., primary, Huang, Ruili, primary, Iannotti, Mike, primary, Karavadhi, Surendra, primary, Klumpp-Thomas, Carleen, primary, Roth, Jacob, primary, Sakamuru, Srilatha, primary, Sun, Wei, primary, Titus, Steven A., primary, Yasgar, Adam, primary, Zhang, Ya-Qin, primary, Zhao, Jinghua, primary, Andrade, Rodrigo B., primary, Brown, M. Kevin, primary, Burns, Noah Z., primary, Cha, Jin K., primary, Mevers, Emily E., primary, Clardy, Jon, primary, Clement, Jason A., primary, Crooks, Peter A., primary, Cuny, Gregory D., primary, Ganor, Jake, primary, Moreno, Jesus, primary, Morrill, LucasA., primary, Picazo, Elias, primary, Susick, Robert B., primary, Garg, Neil K., primary, Goess, Brian C., primary, B. Grossman, Robert, primary, Hughes, ChambersC., primary, Johnston, Jeffrey N., primary, Joullié, Madeleine M., primary, Kinghorn, A. Douglas, primary, Kingston, David G.I., primary, Krische, Michael J., primary, Kwon, Ohyun, primary, Maimone, Thomas J., primary, Majumdar, Susruta, primary, Maloney, Katherine N., primary, Mohamed, Enas, primary, Murphy, Brian T., primary, Nagorny, Pavel, primary, Olson, David E., primary, Overman, Larry E., primary, Brown, Lauren E., primary, Snyder, John K., primary, A. Porco, Jr., John, primary, Rivas, Fatima, primary, Ross, Samir A., primary, Sarpong, Richmond, primary, Sharma, Indrajeet, primary, Shaw, Jared T., primary, Xu, Zhengren, primary, Shen, Ben, primary, Shi, Wei, primary, Stephenson, Corey, primary, Verano, Alyssa L., primary, Tan, Derek S., primary, Tang, Yi, primary, Taylor, Richard E., primary, Thomson, Regan J., primary, Vosburg, David A., primary, Wu, Jimmy, primary, Wuest, William M., primary, Zakarian, Armen, primary, Zhang, Yufeng, primary, Ren, Tianjing, primary, Zuo, Zhong, primary, Inglese, James, primary, Michael, Sam, primary, Simeonov, Anton, primary, Zheng, Wei, primary, Shinn, Paul, primary, Jadhav, Ajit, primary, Boxer, Matthew B., primary, Hall, Matthew D., primary, Xia, Menghang, primary, Guha, Rajarshi, primary, and Rohde, Jason M., primary

Published
2018
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32. High-throughput screening with nucleosome substrate identifies small-molecule inhibitors of the human histone lysine methyltransferase NSD2

Author

Coussens, Nathan P., primary, Kales, Stephen C., additional, Henderson, Mark J., additional, Lee, Olivia W., additional, Horiuchi, Kurumi Y., additional, Wang, Yuren, additional, Chen, Qing, additional, Kuznetsova, Ekaterina, additional, Wu, Jianghong, additional, Chakka, Sirisha, additional, Cheff, Dorian M., additional, Cheng, Ken Chih-Chien, additional, Shinn, Paul, additional, Brimacombe, Kyle R., additional, Shen, Min, additional, Simeonov, Anton, additional, Lal-Nag, Madhu, additional, Ma, Haiching, additional, Jadhav, Ajit, additional, and Hall, Matthew D., additional

Published
2018
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34. Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors

Author

Rohde, Jason M., primary, Brimacombe, Kyle R., additional, Liu, Li, additional, Pacold, Michael E., additional, Yasgar, Adam, additional, Cheff, Dorian M., additional, Lee, Tobie D., additional, Rai, Ganesha, additional, Baljinnyam, Bolormaa, additional, Li, Zhuyin, additional, Simeonov, Anton, additional, Hall, Matthew D., additional, Shen, Min, additional, Sabatini, David M., additional, and Boxer, Matthew B., additional

Published
2018
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36. Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)

Author

Rai, Ganesha, primary, Brimacombe, Kyle R., additional, Mott, Bryan T., additional, Urban, Daniel J., additional, Hu, Xin, additional, Yang, Shyh-Ming, additional, Lee, Tobie D., additional, Cheff, Dorian M., additional, Kouznetsova, Jennifer, additional, Benavides, Gloria A., additional, Pohida, Katie, additional, Kuenstner, Eric J., additional, Luci, Diane K., additional, Lukacs, Christine M., additional, Davies, Douglas R., additional, Dranow, David M., additional, Zhu, Hu, additional, Sulikowski, Gary, additional, Moore, William J., additional, Stott, Gordon M., additional, Flint, Andrew J., additional, Hall, Matthew D., additional, Darley-Usmar, Victor M., additional, Neckers, Leonard M., additional, Dang, Chi V., additional, Waterson, Alex G., additional, Simeonov, Anton, additional, Jadhav, Ajit, additional, and Maloney, David J., additional

Published
2017
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37. Small Molecule Inhibitors of the Human Histone Lysine Methyltransferase NSD2 / WHSC1 / MMSET Identified from a Quantitative High-Throughput Screen with Nucleosome Substrate

Author

Coussens, Nathan P., primary, Kales, Stephen C., additional, Henderson, Mark J., additional, Lee, Olivia W., additional, Horiuchi, Kurumi Y., additional, Wang, Yuren, additional, Chen, Qing, additional, Kuznetsova, Ekaterina, additional, Wu, Jianghong, additional, Cheff, Dorian M., additional, Chih-Chien Cheng, Ken, additional, Shinn, Paul, additional, Brimacombe, Kyle R., additional, Shen, Min, additional, Simeonov, Anton, additional, Ma, Haiching, additional, Jadhav, Ajit, additional, and Hall, Matthew D., additional

Published
2017
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38. Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays

Author

Urban, Daniel J., primary, Martinez, Natalia J., additional, Davis, Mindy I., additional, Brimacombe, Kyle R., additional, Cheff, Dorian M., additional, Lee, Tobie D., additional, Henderson, Mark J., additional, Titus, Steven A., additional, Pragani, Rajan, additional, Rohde, Jason M., additional, Liu, Li, additional, Fang, Yuhong, additional, Karavadhi, Surendra, additional, Shah, Pranav, additional, Lee, Olivia W., additional, Wang, Amy, additional, McIver, Andrew, additional, Zheng, Hongchao, additional, Wang, Xiaodong, additional, Xu, Xin, additional, Jadhav, Ajit, additional, Simeonov, Anton, additional, Shen, Min, additional, Boxer, Matthew B., additional, and Hall, Matthew D., additional

Published
2017
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41. Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors

Author

Singh, Anju, primary, Venkannagari, Sreedhar, additional, Oh, Kyu H., additional, Zhang, Ya-Qin, additional, Rohde, Jason M., additional, Liu, Li, additional, Nimmagadda, Sridhar, additional, Sudini, Kuladeep, additional, Brimacombe, Kyle R., additional, Gajghate, Sachin, additional, Ma, Jinfang, additional, Wang, Amy, additional, Xu, Xin, additional, Shahane, Sampada A., additional, Xia, Menghang, additional, Woo, Juhyung, additional, Mensah, George A., additional, Wang, Zhibin, additional, Ferrer, Marc, additional, Gabrielson, Edward, additional, Li, Zhuyin, additional, Rastinejad, Fraydoon, additional, Shen, Min, additional, Boxer, Matthew B., additional, and Biswal, Shyam, additional

Published
2016
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42. Erratum: Corrigendum: A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate

Author

Pacold, Michael E, primary, Brimacombe, Kyle R, additional, Chan, Sze Ham, additional, Rohde, Jason M, additional, Lewis, Caroline A, additional, Swier, Lotteke J Y M, additional, Possemato, Richard, additional, Chen, Walter W, additional, Sullivan, Lucas B, additional, Fiske, Brian P, additional, Cho, Steve, additional, Freinkman, Elizaveta, additional, Birsoy, Kıvanç, additional, Abu, Monther-Remaileh, additional, Shaul, Yoav D, additional, Liu, Chieh Min, additional, Zhou, Minerva, additional, Koh, Min Jung, additional, Chung, Haeyoon, additional, Davidson, Shawn M, additional, Luengo, Alba, additional, Wang, Amy Q, additional, Xu, Xin, additional, Yasgar, Adam, additional, Liu, Li, additional, Rai, Ganesha, additional, Westover, Kenneth D, additional, Heiden, Matthew G Vander, additional, Shen, Min, additional, Gray, Nathanael S, additional, Boxer, Matthew B, additional, and Sabatini, David M, additional

Published
2016
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43. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate

Author

Pacold, Michael E, primary, Brimacombe, Kyle R, additional, Chan, Sze Ham, additional, Rohde, Jason M, additional, Lewis, Caroline A, additional, Swier, Lotteke J Y M, additional, Possemato, Richard, additional, Chen, Walter W, additional, Sullivan, Lucas B, additional, Fiske, Brian P, additional, Cho, Steve, additional, Freinkman, Elizaveta, additional, Birsoy, Kıvanç, additional, Abu-Remaileh, Monther, additional, Shaul, Yoav D, additional, Liu, Chieh Min, additional, Zhou, Minerva, additional, Koh, Min Jung, additional, Chung, Haeyoon, additional, Davidson, Shawn M, additional, Luengo, Alba, additional, Wang, Amy Q, additional, Xu, Xin, additional, Yasgar, Adam, additional, Liu, Li, additional, Rai, Ganesha, additional, Westover, Kenneth D, additional, Vander Heiden, Matthew G, additional, Shen, Min, additional, Gray, Nathanael S, additional, Boxer, Matthew B, additional, and Sabatini, David M, additional

Published
2016
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45. 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase

Author

Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Israelsen, William J., Vander Heiden, Matthew G., Walsh, Martin J., Brimacombe, Kyle R., Veith, Henrike, Bougie, James M., Daniel, Thomas, Leister, William, Cantley, Lewis C., Shen, Min, Auld, Douglas S., Thomas, Craig J., Boxer, Matthew B., Israelsen, William James, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Israelsen, William J., Vander Heiden, Matthew G., Walsh, Martin J., Brimacombe, Kyle R., Veith, Henrike, Bougie, James M., Daniel, Thomas, Leister, William, Cantley, Lewis C., Shen, Min, Auld, Douglas S., Thomas, Craig J., Boxer, Matthew B., and Israelsen, William James

Abstract

Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described., National Human Genome Research Institute (U.S.) (Molecular Libraries Initiative of the NIH Roadmap for Medical Research)

Published
2015

46. Identification of ML251, a Potent Inhibitor of T. brucei and T. cruziPhosphofructokinase

Author

UCL - SSS/DDUV - Institut de Duve, Brimacombe, Kyle R., Walsh, Martin J., Liu, Li, Vasquez-Valdivieso, Montserrat G., Morgan, Hugh P., McNae, Iain, Fothergill-Gilmore, Linda A., Michels, Paul A.M., Auld, Douglas S., Simeonov, Anton, Walkinshaw, Malcolm D., Shen, Min, Boxer, Matthew B., UCL - SSS/DDUV - Institut de Duve, Brimacombe, Kyle R., Walsh, Martin J., Liu, Li, Vasquez-Valdivieso, Montserrat G., Morgan, Hugh P., McNae, Iain, Fothergill-Gilmore, Linda A., Michels, Paul A.M., Auld, Douglas S., Simeonov, Anton, Walkinshaw, Malcolm D., Shen, Min, and Boxer, Matthew B.

Abstract

Human African Trypanosomiasis (HAT) is a severe, often fatal disease caused by the parasitic protist Trypanosoma brucei. The glycolytic pathway has been identified as the sole mechanism for ATP generation in the infective stage of these organisms, and several glycolytic enzymes, phosphofructokinase (PFK) in particular, have shown promise as potential drug targets. Herein, we describe the discovery of ML251, a novel nanomolar inhibitor of T. brucei PFK, and the structure−activity relationships within the series.

Published
2014

48. Inhibition of Glutathione Peroxidase Mediates the Collateral Sensitivity of Multidrug-resistant Cells to Tiopronin

Author

Hall, Matthew D., primary, Marshall, Travis S., additional, Kwit, Alexandra D.T., additional, Miller Jenkins, Lisa M., additional, Dulcey, Andrés E., additional, Madigan, James P., additional, Pluchino, Kristen M., additional, Goldsborough, Andrew S., additional, Brimacombe, Kyle R., additional, Griffiths, Gary L., additional, and Gottesman, Michael M., additional

Published
2014
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49. Identification of selective inhibitors of phosphofructokinase as lead compounds against trypanosomiasis

Author

UCL - SSS/DDUV - Institut de Duve, Walsh, Martin J., Brimacombe, Kyle R., Vasquez-Valdivieso, Montserrat G., Auld, Douglas S., Simeonov, Anton, Mogan, Hugh P., Fothergill-Gilmore, Linda A., Michels, Paulus, Walkinshaw, Malcolm D., Shen, Min, Boxer, Matthew B., UCL - SSS/DDUV - Institut de Duve, Walsh, Martin J., Brimacombe, Kyle R., Vasquez-Valdivieso, Montserrat G., Auld, Douglas S., Simeonov, Anton, Mogan, Hugh P., Fothergill-Gilmore, Linda A., Michels, Paulus, Walkinshaw, Malcolm D., Shen, Min, and Boxer, Matthew B.

Abstract

The protist Trypansoma brucei is the causative agent of Human African Trypanosomiasis (HAT), a disease that is endemic to sub-Saharan Africa and is responsible for approximately 50,000 deaths each year worldwide. Current therapies employed to treat HAT generally suffer from poor selectivity profiles, and consequently, lead to high rates of deleterious side effects. Furthermore, growing resistance to these drugs has highlighted a need for the identification of novel therapies. The glycolytic enzyme phosphofructokinase (PFK) has been recognized as a potential therapeutic target in the fight against the bloodstream form of T. brucei due to the reliance of this parasite on the metabolism of glucose as its sole mechanism for the generation of adenosine triphosphates (ATP). The importance of this enzyme has been confirmed by genetic validation, and thus, its inhibition may represent a novel strategy for the treatment of HAT. Currently, no inhibitors of Tb PFK have been described that possess ideal drug-like qualities or submicromolar potency in either enzymatic or live parasite culture assays. As a result, in collaboration with Professor Malcolm Walkinshaw of the University of Edinburgh, a quantitative High Throughput Screening (qHTS) campaign was initiated at the NIH Chemical Genomics Center to identify novel small molecule inhibitors of Tb PFK. The primary screen utilized a firefly luciferase-coupled assay specifically designed to monitor the production of ADP in the kinase reaction. This work, together with subsequent medicinal chemistry efforts, has identified a novel small molecule inhibitor (ML251) of Tb PFK, which is described herein to possess potent activity in enzymatic assays (IC50 = 370 nM) and toxicity against cultured T. brucei (ED50 = 16.3 M). This compound has been subjected to a panel of in vitro absorption, distribution, metabolism, and excretion (ADME) assays and delivers a promising profile in this respect. Finally, cytotoxicity evaluations against MR

Published
2013

50. Structure-Activity Relationship of Imidazopyridinium Analogues as Antagonists of Neuropeptide S Receptor

Author

Patnaik, Samarjit, Marugan, Juan J., Liu, Ke, Zheng, Wei, Southall, Noel, Dehdashti, Seameen J., Thorsell, Annika, Heilig, Markus, Bell, Lauren, Zook, Michelle, Eskay, Bob, Brimacombe, Kyle R., Austin, Christopher P., Patnaik, Samarjit, Marugan, Juan J., Liu, Ke, Zheng, Wei, Southall, Noel, Dehdashti, Seameen J., Thorsell, Annika, Heilig, Markus, Bell, Lauren, Zook, Michelle, Eskay, Bob, Brimacombe, Kyle R., and Austin, Christopher P.

Abstract

The discovery and characterization of a novel chemical series of phosphorothioyl-containing imidazopyridines as potent neuropeptide S receptor antagonists is presented. The synthesis of analogues and their structure-activity relationship with respect to the Gq, Gs, and ERK pathways is detailed. The pharmacokinetics and in vivo efficacy of a potent analogue in a food intake rodent model are also included, underscoring its potential therapeutic value for the treatment of sleep, anxiety, and addiction disorders.

Published
2013
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