Faculty

Jolanta Grembecka

Assistant Professor of Pathology

Ph.D., Wroclaw University of Technology, Poland
Postdoctoral Fellow, University of Virginia

Research Focus: Drug design, Development of small molecules for targeted therapies in cancer, Protein-protein interactions

Phone: 734.615.9319
E-mail: jolantag@umich.edu
Fax: 734.615.0688

Our research is focused on using chemical biology approaches to develop small molecules that could serve as either chemical probes or new potential therapeutics for cancer. We are using different strategies for identification of lead compounds, including fragment-based approach, high throughput screening, and virtual screening. A broad collection of biochemical, biophysical, medicinal chemistry, computational and structural biology methods is being used in our laboratory for lead optimization. Furthermore, we use cell biology methods for functional assays to evaluate compound effectiveness in human cancer cell lines and patient samples, as well as in vivo biology studies to test these compounds in mouse models of cancer, both leukemia and solid tumors.

Our primary focused is to target proteins involved in oncogenesis, with a particular interest in leukemia-related proteins. Currently, we are developing small molecules to inhibit MLL fusion proteins in leukemia by blocking the protein-protein interaction between menin and MLL. We developed very potent menin-MLL inhibitors, which block proliferation and induce differentiation of leukemia cells and demonstrate strong efficacy in mouse models of MLL leukemia. Our current efforts are focused on further advancement of these compounds to develop clinically useful compounds and on exploration of their effect in other cancer models. Ultimately, such compounds may provide a novel therapeutic strategy for acute leukemia and possibly for solid tumors.

We are also interested in developing small molecules targeting other proteins involved in oncogenesis. This includes Cdc25 phosphatases, which activate cyclin-dependent kinases (Cdks) by dephosphorylating critical phospho-tyrosine and phospho-threonine residues on these proteins. Cdc25s enhance cell proliferation and oncogenesis, and overexpression of Cdc25A and/or B occurs in several types of primary human cancers, including breast, prostate and pancreatic cancers. Therefore, selective inhibition of Cdc25 phosphatases by small molecules we are developing might result in novel anti-cancer agents.

 

Awards

2014
University of Michigan League of Research Excellence Inductee
2013
LLS Scholar Recipient
2013
ACS Research Scholar Recipient

 


Representative Publications

  1. Borkin D, He S, Miao H, Pollock J, Chase J, Zhao T, Wang J, Purohit T, Wen B, Zong H, Jones M, Danet-Desnoyers G, Guzman ML, Talpaz M, Bixby DL, Sun D, Hess JL, Muntean AG, Maillard I, Cierpicki T, Grembecka J*: Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell, 27(4): 589-602, 2015.

  2. He S, Malik B, Borkin D, Miao H, Shukla S, Kempinska K, Purohit T, Wang J, Chen, L., Parkin B, Malek S.N, Danet-Desnoyers G, Muntean AG, Cierpicki T, Grembecka J* Menin-MLL inhibitors block oncogenic transformation by MLL fusion proteins in a fusion partner independent manner. Leukemia, 2015, Jun 18. doi: 10.1038/leu.2015.144. [Epub ahead of print].

  3. Illendula A, Pulikkan JA, Zong H, Grembecka J, Xue L, Sen S, Zhou Y, Boulton A, Kuntimaddi A, Gao Y, Rajewski RA, Guzman ML, Castilla LH, Bushweller JH: Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science, 347(6223): 779-84, 2015.

  4. S. He, T.J. Senter, J. Pollock, C. Han, S. K. Upadhyay, T. Purohit, R. D. Gogliotti, C.W. Lindsley, T. Cierpicki, S. R. Stauffer, J. Grembecka*, High-affinity small molecule inhibitors of the menin-Mixed Lineage Leukemia (MLL) interaction closely mimic a natural protein-protein interaction, J. Med. Chem., (2014), 57 (4), 1543-56

  5. Grembecka J*, He S, Shi A, Purohit T, Muntean AG, Sorenson RJ, Showalter HD, Murai M, Belcher A, Hartley T, Hess JL, Cierpicki T. (2012) Menin-MLL Inhibitors Reverse Oncogenic Activity of MLL Fusion Proteins in Leukemia. Nature Chem. Biol, 8, 277-284

 

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