Eldar-Finkelman’s research is focused on the signal transduction field and drug development targeting protein kinases. She is well known for her pioneering work on the functions of GSK-3 and its contribution to diabetes and other pathogenies, including depressive behavior Alzheimer’s disease, and Huntington’s disease. Novel findings also include the unique evolution of GSK-3 isozymes. Eldar-Finkelman is a leading figure in developing novel substrate competitive inhibitors (SCIs) for GSK-3 with significant benefits as drug candidates.
פרופ' חגית אלדר-פינקלמן
סגל אקדמי בכיר בגנטיקה מולקולרית של אדם וביוכימיה
מופקד על קתדרה בדיקאנט ומנהל הפקולטה לרפואה
ממלא מקום חבר ועדת המינויים האוניברסיטאית בדיקאנט ומנהל הפקולטה לרפואה
גנטיקה מולקולרית של אדם וביוכימיה
סגל אקדמי בכיר
מופקד על קתדרה בדיקאנט ומנהל הפקולטה לרפואה
ממלא מקום חבר ועדת המינויים האוניברסיטאית בדיקאנט ומנהל הפקולטה לרפואה
דואר אלקטרוני: heldar@tauex.tau.ac.il
טלפון פנימי: 03-6405307
טלפון נוסף: 03-6405308
פקס: 03-6408749
משרד: רפואה-סאקלר, 1012
מידע כללי
Biography
Education
| 1994 – 1998 | Postdoctoral work with Nobel Laureate Professor Edwin G Krebs | School of Medicine, University of Washington (UW) |
| 1993 | Doctor of Philosophy (Ph.D.), Life Science | Weizmann Institute of Science |
| 1988 | Recipient of the British Council Award to conduct research in biological nuclear magnetic resonance | University of Oxford |
| 1988 | M.Sc., Chemsitry | Weizmann Institute of Science |
| 1982 | B.Sc., Chemistry | The Hebrew University |
Research
Eldar-Finkelman’s research is focused on the signal transduction field and drug development targeting protein kinases. She is well known for her pioneering work on the functions of GSK-3 and its contribution to diabetes and other pathogenies, including depressive behavior Alzheimer’s disease, and Huntington’s disease. Novel findings also include the unique evolution of GSK-3 isozymes. Eldar-Finkelman is a leading figure in developing novel substrate competitive inhibitors (SCIs) for GSK-3 with significant benefits as drug candidates.
The research in Eldar-Finkelman’s laboratory is focused on the development of new innovative therapeutics addressing unmet needs in the cancer neurodegenerative disorders arena. A particular interest is given to the protein kinases such as glycogen synthase kinase-3 (GSK-3), and ABL1 as prominent drug targets. We combine expertise in chemistry, biology, and computational modeling to design drugs with unique inhibition /modality. Our goal is to ultimately produce beneficial therapeutics for clinical practice.
Publications and Grants
Articles
- Saper, M.A., Eldar, H., Nickole, J., Appela, E. Sussman, J.L. (1986) Crystalization of a DNA tridecamer. J. Mol. Biol.; 188:111-3.
2. Eldar, H., Degani, H. (1989) 31P NMR studies of the thermodynamics and kinetics of the creatine kinase reaction. J. Magn. Reson. Med.; 11:12126.
3. Seymour, A.M., Eldar, H., Radda, G.K. (1990) Hyperthyrodism results in increased glycolytic capacity in the rat heart. 31P NMR studies. Biochem. Biophys. Acta.;1055:107-16.
4. Neeman, M., Eldar, H., Rushkin, E., Degani, H. (1990) Chemotherapy-induced changes in the energetics of human breast cancer cells, 31P and 13C NMR studies. Biochem. Biophys. Acta.; 1052:55-63.
5. Eldar, H., Zisman, Y., Ullrich, A., Livneh, E. (1990) Overexpression of protein kinase C-a subtype in Swiss/3T3 fibroblasts causes loss of both high and low affinity receptors for epidermal growth factor. J. Biol. Chem. 265:13290-296.
6. Eldar-Finkelman, H., Zisman, Y., Ullrich, A., and Livneh, E. (1990) Overexpression of protein kinase C-a in Swiss/3T3 cells reduces the number of both high and low affinity of the epidermal growth factor Signal Transduction, Vol. 51, p. 271-81: Springer-Verlag press.
7. Raber, J., Eldar, H., Lehrer, R., Chabath, J., Livneh, E. (1991) Regulation of the interferon-induced 100kda 2'-5' A synthetase by A23187 and Protein Kinase C. Eur. Cytokine Net.; 2: 281-90.
8. Greif, H., Ben-Chaim, J., Shimon, T., Bechor, E., Eldar, H., Livneh, E. (1992) The protein kinase C-related PKC-L(eta) gene product is localized in the cell nucleus. Mol. Cell. Biol.; 123:1304-11.
9. Eldar, H,. Ben-Chaim, J., Livne, E. (1992) Deletions in the regulatory or kinase domains of protein kinase C-a causes association with the cell nucleus. Exp. Cell. Res. 202: 259-66.
10. Eldar, H., Livneh, E. (1992) Phosphorylation of p90 and p52 accompanies the response to phorbol esters in Swiss/3T3 cells overexpressing protein kinase C-a. Mol. Biol. Cell. 3:1049-56.
11. Slack, B.E., Nitsch, R.M., Livneh, E. Kunz, G.M., Breu, J., Eldar, H., Wurtman, R.J. (1992) Regulation by phorbol esters of amyloid precursor protein release from Swiss/3T3 fibroblasts overexpressing protein kinase C-a. J. Biol. Chem.; 268:21097-101.
12. Liscovitch, M., Ben-Av, P., Danin, M., Faiman, G., Eldar, H., Livneh, E. (1993) Phospholipase D-mediated hydrolysis of phosphatidylcholine: Role in cell signaling. J. Lipid Mediators 8:177-82.
13. Eldar, H., Ben-Av, P., Schmidt, U.S., Livneh, E., Liscovitch, M. (1993) Up-regulation of phospholipase D activity induced by overexpression of protein kinase C-a. Studies in intact Swiss/3T3 cells and in detergent-solubilized membranes in vitro J. Biol. Chem. 268:12560-64.
14. Slack, B.E., Nitsch, R.M., Livneh, E., Kunz, G.M. Jr, Eldar, H., Wurtman, R.J. (1993) Regulation of amyloid precursor protein release by protein kinase C in Swiss 3T3 fibroblasts. Ann N Y Acad Sci. 695:128-31.
15. Fitzer-Attas, C., Eldar, H., Eisenbach, L., Livneh, E. (1994) Expression of PDGF-a but not PDGF-b receptor is regulated in protein kinase C-a overexpressing Swiss/3T3 fibroblasts. FEBS-Lett. 342:165-70.
16. Seger, R., Seger, D., Reszka, A.A., Munar, E.S., Eldar-Finkelman, H., Dobrowolska, G., Jensen, A.M., Campbell, J.S., Fischer E.H., Krebs, E.G. (1994) Overexpression of mitogen-activated protein kinase kinase (MAPKK) and its mutants in NIH 3T3 cells. Evidence that MAPKK involvement in cellular proliferation is regulated by phosphorylation of serine residues in its kinase subdomains VII and VIII. J. Biol. Chem. 269:25699-709.
17. Slack, B.E., Breu, J., Livneh E., Eldar, H., Wurtman, R.J. (1995) Phorbol esters stimulate choline uptake in Swiss 3T3 fibroblasts following introduction of the gene encoding protein kinase C a. Biochem. .J. 305: 621-6.
18. Eldar-Finkelman H., Seger, R., Vandenheede, J .R., Krebs, E.G. (1995) inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. J. Biol. Chem. 270:987-90.
19. Eldar-Finkelman, H., Agrast G.M., Foord O., Fischer E.H. Krebs E.G. (1996) Expression and characterization of glycogen synthase kinase-3 mutants and their effect on glycogen synthase activity. Proc. Natl. Acad. Sci. USA 93:10228-33.
20. Eldar-Finkelman H., Krebs E.G. (1997) Phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 impairs insulin action. Proc. Natl. Acad. Sci. USA 94:9660-64.
21. Torres M., Eldar-Finkelman, H. Krebs, E.G. Moon, R.T. (1999) Regulation of S6 ribosomal protein kinase p90 RSK, glycogen synthase kinase-3 and b-catenin in Early Xenopus Development. Mol. Cell Biol. 19:1427-37.
22. Eldar-Finkelman H. Schreyer, S.A., M.M. Shinohara, M.M., Leboeuf, R.C., Krebs, E.G. (1999) Increased glycogen synthase kinase-3 activity in diabetes and obesity prone C57BL/6J mice Diabetes 48:1662-1666.
23. Zhao, A.Z., Shinohara, M.M., Huang, D., Shimizu, M., Eldar-Finkelman, H. Krebs, E.G., Beavo, J.V., Bornfeldt, K.E. (2000) Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. J. Biol. Chem. 275:11348-54.
24. Hall, J.L., Chatham, J.C., Eldar-Finkelman H., Gibbons, H. (2001) Upregulation of glucose metabolism during intimal lesion formation is coupled to the inhibition of vascular smooth muscle cell apoptosis: role of GSK-3b. Diabetes 50:1171-9
25. Ilouz, R., Kaidanovich, O., Gurwitz, D., Eldar-Finkelman, H. (2002) Inhibition of glycogen synthase kinase-3b by bivalent zinc ions: insights into the insulin-mimetic action of zinc. Biochem. Biophys. Res. Commun. 295:102-106.
26. Plotkin B., Kaidanovich, O., Talior, I. Eldar-Finkelman, H. (2003) Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3. J. Pharmacol. Exp. Ther. 305:974-980.
27. Talior, I., Yarkoni, M., Bashan, N., Eldar-Finkelman, H. (2003) Increased gGlucose uptake promotes Oxidative Stress and Activation of Protein Kinase C-d in Adipocytes of obese and insulin-resistant C57Bl/6J Mice. Am. J. Physiol. Endocrin. Metab. 285:E295-E302.
28. Kaidanovich-Beilin, O., Milman, A., Pick, C., Weizman, A., Eldar-Finkelman, H. (2004) Rapid anti-depressive like activity of specific GSK-3 inhibitor, and its effect on b-catenin in the mouse hippocampus. Biol. Psychiatry 55:781-784.
29. Kirshennboim, N., Plotkin, B., Ben Shlomo, S., Kaidanovich-Beilin, O., Eldar-Finkelman, H. (2004) Lithium-mediated phosphorylation of glycogen synthase kinase-3 involves PI3 Kinase-dependent activation of protein kinase C-a. J. Mol. Neuroscience, 24, 199-207.
30. Tailor, I. Tennenbaum , T., Kuroki, T. Eldar-Finkelman, H. (2005) Protein kinase C-d dependent activation of oxidative stress in adipocytes of Insulin resistant and obese mice: role for NADPH oxidase. Am. J. Physiol. Endocrinol. Metab. 288:E405-11.
31. Liberman Z. and Eldar-Finkelman, H. (2005) Serine332 Phosphorylation of insulin receptor substrate-1 by GSK-3-3 attenuates insulin signaling. J. Biol. Chem. 280:4422-8.
32. Kaidanovich-Beilin, O. and Eldar-Finkelman, H. (2006) Long-term treatment with novel GSK-3 inhibitor improves glucose homeostasis in Ob/Ob Mice: Molecular characterization in liver and muscle. J. Pharmacol. Exp. Ther. 316:17-24.
33. Ilouz, R., Kowalsman, N., Eisenstein, M., Eldar-Finkelman, H. (2006) Identification of novel GSK-3b substrate interacting residues suggests a common mechanism for substrates recognition. J. Biol. Chem. 281:30621-30.
34. Shapira, M. Licht, A. Milman, A. Pick,C.G., Shohami, E. Eldar-Finkelman, H. (2007) Role of GSK-3b in early depressive behavior Induced by mild traumatic brain injury. Mol. Cell. Neuroscience. 34:571-577.
35. Erez A, Castiel A, Trakhtenbrot L, Perelman M, Rosenthal E,Goldstein I, Stettner N, Harmelin A, Eldar-Finkelman H, Campaner S, Kirsch I, Izraeli S. (2007) The SIL gene is essential for mitotic entry and survival of cancer cells. Cancer Res. 67:4022-4027.
36. Sharfi, H. Eldar-Finkelmnan, H. (2007) Sequential phosphorylation of insulin receptor substrate-2 by GSK-3 and c-Jun N-terminal kinase plays a role in hepatic insulin signaling Am. J. Physiol. Endocrinol. Metab. 2008, 294: E307-15.
37. Caspi, M., Zilberberg , A. Eldar-Finkelman, H., Rosin-Arbesfeld, R. (2008) Nuclear GSK-3b inhibits the canonical Wnt signalling pathway in a beta-catenin phosphorylation-independent manner. Oncogene. 27:3546-3555.
38. Liberman Z. Plotkin, B. Eldar-Finkelman, H. (2008) Coordinated phosphorylation of insulin receptor Substrate-1 by GSK-3 and protein kinase CbII at in the diabetic fat tissue. Am. J. Physiol. Endocrinol. Metab. 294:E1169-1177.
39. Ilouz, R, Pietrokovsky, S, Eisenstein, M, Eldar-Finkelman, H. (2008) New Insights into the autoinhibition mechanism of GSK-3b. J. Mol. Biol. 385:999-1007.
40. Watson, RL Spalding, AC, Zielske, PS, Morgan, M, Kim, AC Guido Bommer,T, Eldar-Finkelman, H, Giordano, T, Fearon, ER, Hammer, GD, Lawrence, TS and Ben-Josef, E. (2010) GSK3b and b-catenin modulate radiation cytotoxicity in pancreatic cancer. Neoplasia, 357-365.
41. Leng, S., Zhang, W., Zheng, Y., Liberman, Z., Rhodes, C.J., Eldar-Finkelman, H., and Sun, X.J. (2010) GSK-3b mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. J Endocrinol 206, 171-181.
42. Karyo, R., Eskira, Y., Pinhasov, A., Belmaker, R., Agam, G., and Eldar-Finkelman, H. (2010) Identification of eukaryotic elongation factor-2 as a novel cellular target of lithium and GSK-3. Mol. Cell Neurosci. 45, 449-455.
43. Shruster, A., Eldar-Finkelman, H., Melamed, E., Offen, D. (2011) Wnt signaling pathway overcomes the disruption of neurogenesis induced by oligomeric amyloid ß-peptide. J. Neurochem. 116: 552-559.
44. Azoulay-Alfaguter, I. Yaffe, Y., Licht-Murava, A., Urbanska, M., Jaworski, J., Pietrokovski, S., Hirschberg, K. Eldar-Finkelman, H. (2011) Distinct molecular regulation of GSK-3a controlled by it N-terminal region. Functional role in calcium/calpain signaling. J. Biol. Chem. 286:13470-13480
45. Licht-Murava, A., Plotkin, B., Eisenstein, M., Eldar-Finkelman, H. (2011) Elucidating substrate and Inhibitor binding sites on the surface of GSK-3b and the refinement of a competitive inhibitor. J. Mol. Biol. 408:366-378
46. Tsaadon Alon, L., Pietrokovski, S., Barkan, S., Avrahami, L. Kaidanovich-Beilin, O., Woodgett, J. Barnea, A., Eldar-Finkelman, H. (2011) Selective Loss of GSK-3a in birds reveals distinct roles for GSK-3 Isozymes in tau phosphorylation. FEBS Lett. 585:1158-1162.
47. Monte, LM, Kramer, T. Boländer, A. Plotkin, B., Eldar-Finkelman, H., Fuertes, A., Dominguez, D., Schmidt, B. (2011) Synthesis and biological evaluation of glycogen synthase kinase 3 (GSK-3) inhibitors: an fast and atom efficient access to 1-aryl-3-benzylureas. Bioorg. Med. Chem. Lett. 21:5610-5615.
48. Monte, LM, Kramer, T., Gu, J., Anumala, R. Marinelli, L., La Pietra, V., Novellino, E., Franco, B., Demedts, D., an Leuven, F., Fuertes, A., Dominguez, JM., , Plotkin, B., Eldar-Finkelman, H., Schmidt, B. 2012, Identification of Glycogen Synthase Kinase-3 Inhibitors with a Selective Sting for Glycogen Synthase Kinase-3α. (2012) J. Med. Chem. 55:4407-4424.
49. Monte, LM, Kramer, T., Gu, J., Brodecht, M., Fuertes, Dominguez, JM., , Plotkin, B., Eldar-Finkelman, H., Schmidt, B. (2012) Structure-based optimization of oxadiazole-based GSK-3 inhibitors. Eur. J. Med. Chem. 55:4407-4424.
50. Avrahami, L. Farfara, D., Shaham-Kol, M., Vassar, R., Frenkel, D., Eldar-Finkelman, H. (2013) Inhibition of GSK-3 Ameliorates b-Amyloid (Ab) Pathology and Restores Lysosomal Acidification and mTOR Activity in the Alzheimer’s Disease Mouse Model. In vivo and In vitro Studies. J. Biol. Chem. 288:1295-1306.
51. Beurel, E., Kaidanovich-Beilin, O., Yeh, W., Song, L, Palomo, V., Michalek, SM., Woodgett, JR, Harrington, LE, Eldar-Finkelman, H., Martinez, A., Jope, RS. (2013), Regulation of Th1 cells and experimental autoimmune encephalomyelitis (EAE) by GSK-3. J. Immunol. 190:5000-5011.
52. Avrahami, L., Eldar-Finkelman, H. 2013, GSK-3 and lysosomes meet in Alzheimer’s disease. Communicative & Integrative Biology. 6:e251789
53. La Pietra V., La Regina, G., Coluccia, A., Famiglini. V., Pelliccia, S., Plotkin, B., Eldar-Finkelman, H., Brancale, A., Ballatore, C., Crowe, A., Brunden, KR., Marinelli, L,. Novellino, E., Silvestri R. (2013) Design, Synthesis, and Biological Evaluation of 1-Phenylpyrazolo[3,4-e]pyrrolo[3,4-g]indolizine-4,6(1H,5H)-diones as New Glycogen Synthase Kinase-3β Inhibitors. J. Med Chem. 56: 10066-10078.
54. Azoulay-Alfaguter I, Elya R, Avrahami L, Katz A, Eldar-Finkelman H. (2015) Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses autophagy and contributes to cancer cells growth. Oncogene. 34: 4613-4623.
55. Aloni, E., Shapira, M., Eldar-Finkelman, H., Barnea, A. (2015) GSK-3β inhibition affects Singing behavior and neurogenesis in adult songbirds. Brain, Behavior and Evolution. 85: 233-244.
56. Licht-Murava, A., Paz, R., Vaks L., Avrahami, L., Plotkin,B., Eisenstein, M., Eldar-Finkelman,H. (2016) A unique type of GSK-3 inhibitor brings new opportunities to the clinic. Sci Signal, 9(454), ra110. (selected as breakthrough of the year).
57. Grieco, S.F., Velmeshev, D. Magistri, M. Eldar-Finkelman, H., Faghihi, M. A., Jope, R. S. Beurel, E. (2016) Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3. World J Biol Psychiatry, 1-12 (2017).
58. Grieco, S.F., Cheng, Y., Eldar-Finkelman, H., Jope, R.S., Beurel,E. (2017) Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition. Prog Neuropsychopharmacol Biol Psychiatry 72: 49-54.
59. Pardo, M., Cheng, Y., Velmeshe, D., Magistri, M., Eldar-Finkelman, H., Martinez, A., Faghihi, M.A., Jope, R.S., Beurel,E. (2017) Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice. JCI Insight 2:e91782.
60. Avrahami, L., Paz, R., Dominko, Silva Hecimovic, S., Bucci, C., Eldar-Finkelman, H. (2020) GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways. Cell. Signal. 71: 109597.
61. Rippin, I., Khazanov, N., Ben Joseph, S., Kudinov, T., Berent, E., Arciniegas Ruiz, S-M., Marciano, D., Levy, L., Gruzman, A., Senderowitz, Eldar-Finkelman, H. (2021) Discovery and design of novel small molecule GSK-3 inhibitors targeting the substrate binding site. (IJMS, 21: 8709.
62. Rippin, I., Boner, K., Joseph, S., Sarsor, A., Vaks, L., Eldar-Finkelman, H. (2021) Inhibition of GSK-3 ameliorates the pathogenesis of Huntington's disase. Neurobiology of Disease, 154, 105336.
63. Moaraf, F., Rippin, I., Terkel, J., Eldar-Finkelman, H., Barnea, A. (2022) GSK-3β inhibition in birds affects social behavior and increases motor activity Frontiers Physiology, in press.
Reviews
64. Eldar-Finkelman, H. (2002) GSK-3: an emerging therapeutic target. Trends Mol. Med, 8:126-132.
65. Gurwitz, D. Eldar-Finkelman, H. (2002) GSK-3 inhibitors: potential drugs for neurodegenerative disorders. Drug Discovery Today 6: 1072-1074.
66. Kaidanovich-Beilin, O., Eldar-Finkelman, H. (2002) The role of GSK-3 in insulin resistance and type 2 diabetes. Exp. Opin. Ther. Targ. 6:555-561.
67. Eldar-Finkelman, H. Ilouz, R. (2003) Challenges and opportunities with GSK-3 inhibitors in treatment of insulin resistance and type 2 diabetes. Exp. Opin. Invs. Drugs 12 1511-1519.
68. Kaidanovich-Beilin, O., Eldar-Finkelman, H. (2006) Peptides targeting protein kinases-Strategies and implications. Physiology, 21:411-8.
69. Eldar-Finkelman, H. (2010) Eisenstein, M. Peptides inhibitors targeting protein kinases. (2009) Curr. Pharm. Des. 15:2463-2470
70. Licht-Murava, A., Pietrokovski, S. Eisenstein, M, Eldar-Finkelman, H. (2010) Substrate competitive GSK-3 Inhibitors ¾ Strategy and Implications. BBA protein and proteomics. 180: 598-603.
71. Licht-Murava, A., Eldar-Finkelman, H. (2011) Exploiting substrate recognition for selective inhibition of protein kinase. Current Pharma. Des. 18: 2914-2920
72. Eldar-Finkelman, H., Martinez, A. (2011) GSK-3 inhibitors: Preclinical and clinical focus at the CNS. Front. Mol. Neurosci. 4:32.
73. Avrahami, L., Lich-Murava, A., Eisenstein, M., Eldar-Finkelman, H. (2013) GSK-3 Inhibition:achieving moderate efficacy with high selectivity. BBA protein proteomic. 1834: 1410-1414
74. Kllionsky, D.J. et al (2016) Guidelines for the use and interpretation for assay for monitoring autophagy. Autophagy, 12:1-222.
75. Rippin, I., Eldar-Finkelman (2021) Mechanisms and therapeutic implications of GSK-3 in
treating Neurodegeneration. Cells, 10(2): 262.
76. Arciniegas Ruiz, S., Eldar-Finkelman, H. (2022) GSK-3 inhibitors: preclinical and clinical focus
on CNS- A decade onward. Front. Mol. Neurosci. 4:32.
77. Arciniegas Ruiz, S., Rippi, I., Eldar-Finkelman, H. (2022) Editorial: Prospects in GSK-3
Signaling: From Cellular Regulation to Disease Therapy, Cells in press
