Grembecka/Cierpicki Lab

Home Jolanta Grembecka Tomasz Cierpicki Lab Projects Publications Lab Members Positions Available Lab News

Aug 2018

Our finding that GAS41 recognizes di-acetylated histone has been published in ACS Chemical Biology

July 2018

We reported new class of BCL6 inhibitors in J. Med. Chem.

May 2018

We published new series of menin inhibitors in J. Med. Chem.

Jan 2018

We found activity of menin inhibitors in hepatocellular carcinoma (published in Mol. Cancer Ther.)

Nov 2016

We have published paper "BMI1 regulates PRC1 architecture and activity through homo- and hetero-oligomerization" in Nature Communictions.

Sep 2016

We have published review H3K36 methyltransferases as cancer drug targets: rationale and perspectives for inhibitor development in Future Medicinal Chemistry.

We published development of potent BCL6 inhibitor in collaboration with groups from Cornell and University of Maryland.

May 2016

David Rogawski defended his PhD thesis. Congratulations Dave!

 Jan 2016

We published paper "Property focused structure-based optimization of small molecule inhibitors of the protein-protein interaction between menin and Mixed Lineage Leukemia (MLL)" in the Journal of Medicinal Chemistry.

Featured on the cover!

Nov 2015

We determined structure of ZMIZ1 TPR domain and published paper in collaboration with Mark Chiang: The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia. Published in Immunity.

Aug 2015

Our manuscript "Two loops undergoing concerted dynamics regulate activity of the ASH1L histone methyltransferase" has been published in Biochemistry.

Our study "Rational design of orthogonal multipolar interactions with fluorine in protein-ligand complexes" has been published in Journal of Medicinal Chemistry, selected as Editor's choice.

July 2015

Felicia Gray defended her PhD thesis: "Dissecting Bmi1 protein-protein interactions through chemical biology". Congratulations Felicia!

June 2015

We have published study demonstrating that menin-MLL inhibitors block activity of MLL fusion proteins in a mechanism independent on fusion partner. Published in Leukemia.

May 2015

George Lund defended his PhD dissertation: "Targeting CDC25B-CDK2/CyclinA Activity Using Chemical Biology Approaches".

Congratulations George!

April 2015

Our menin-MLL inhibitor program has been featured as cover story in BioCentury Innovations

Dr. Chinnaiyan's lab discovered role of menin and demonstrated efficacy of menin inhibitors in castrate resistant prostate cancer. Study published in Nature Medicine.

March 2015

Our team work resulted in development of potent inhibitors of menin-MLL interaction with strong efficacy in animal models of leukemia. Published in Cancer Cell

We have licensed menin-MLL inhibitors to Kura Oncology for further development.

Feb 2015

Jola is co-author on study to develop small molecule inhibitors of CBFB-SMMHC: "A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice" published in Science.

Jan 2015

We published review Targeting protein–protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies? in Immunological Reviews

Dec 2014

Our study Inhibition of CDC25B Phosphatase Through Disruption of Protein-Protein Interaction has been published in ACS Chemical Biology.

Nov 17th 2014

Jola has been elected to the University of Michigan Medical School "League of Research Excellence". Congratulations to Jola!

Oct 2014

Our study "The same site on LEDGF IBD domain represents therapeutic target for MLL leukemia and HIV" has been published in Blood. 

Apr 21 2014

George's publication "Solution NMR studies reveal no global flexibility in the catalytic domain of CDC25Bhas been published in journal Proteins.

Congratulations to George!

Our review "Challenges and opportunities in targeting the menin-MLL interaction" has been published in Future Medicinal Chemistry

Publications from Grembecka/Cierpicki lab since joining the University of Michigan

24. Cho HJ, Li H, Linhares BM, Kim E, Ndoj J, Miao H, Grembecka J, Cierpicki T. (2018) GAS41 recognizes di-acetylated histone H3 through a bivalent binding mode. ACS Chem Biol. 13(9):2739-2746

23. Cheng H, Linhares BM, Yu W, Cardenas MG, Ai Y, Jiang W, Winkler A, Cohen S, Melnick A, MacKerell A Jr, Cierpicki T, Xue F. (2018) Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design. J Med Chem. 61(17):7573-7588

22. Borkin D, Klossowski S, Pollock J, Miao H, Linhares BM, Kempinska K, Jin Z, Purohit T, Wen B, He M, Sun D, Cierpicki T, Grembecka J. (2018). Complexity of Blocking Bivalent Protein-Protein Interactions: Development of a Highly Potent Inhibitor of the Menin-Mixed-Lineage Leukemia Interaction. J Med Chem. 61(11):4832-4850.

21. Kempinska K, Malik B, Borkin D, Klossowski S, Shukla S, Miao H, Wang J, Cierpicki T, Grembecka J. (2018) Pharmacologic Inhibition of the Menin-MLL Interaction Leads to Transcriptional Repression of PEG10 and Blocks Hepatocellular Carcinoma. Mol Cancer Ther. 17(1):26-38.

20. Grembecka J, Cierpicki T. (2017) Stabilizing the Mixed Lineage Leukemia ProteinN Engl J Med. 376(17):1688-1689.

19. Felicia Gray, Hyo Je Cho, Shirish Shukla, Shihan He, Ashley Harris, Bohdan Boytsov, Łukasz Jaremko, Mariusz Jaremko, Borries Demeler, Elizabeth R. Lawlor, Jolanta Grembecka & Tomasz Cierpicki. (2016) BMI1 regulates PRC1 architecture and activity through homo- and hetero-oligomerization. Nature Communications, 7:13343

18. Rogawski DS, Grembecka J and Cierpicki T. (2016) H3K36 methyltransferases as cancer drug targets: rationale and perspectives for inhibitor development. Future Medicinal Chemistry, 8(13):1589-607

17. Borkin D, Pollock JW, Kempinska K, Purohit T, Li X, Wen B, Zhao T, Miao H, Shukla S, He M, Sun D, Cierpicki T, Grembecka J. (2016) Property focused structure-based optimization of small molecule inhibitors of the protein-protein interaction between menin and Mixed Lineage Leukemia (MLL). J. Med. Chem. 59(3):892-913

16. Rogawski DS, Ndoj J, Cho HJ, Maillard I, Grembecka J, Cierpicki T. (2015) Two loops undergoing concerted dynamics regulate activity of the ASH1L histone methyltransferase. Biochemistry 54(35):5401-13

15. Pollock JW, Borkin D, Lund G, Purohit T, Dyguda-Kazimierowicz E, Grembecka J, Cierpicki T. (2015) Rational design of orthogonal multipolar interactions with fluorine in protein-ligand complexes. J Med Chem. 58(18):7465-74

Selected as Editor's choice. Please contact us for free version of FMAP.

14. He S, Malik B, Borkin D, Miao H, Shukla S, Kempinska K, Purohit T, Wang J, Chen L, Parkin B, Malek SN, Danet-Desnoyers G, Muntean AG, Cierpicki T, Grembecka J. (2015) Menin-MLL inhibitors block oncogenic transformation by MLL-fusion proteins in a fusion partner-independent manner. Leukemia, 30(2):508-13

13Borkin D, He S, Miao H, Kempinska K, Pollock J, Chase J, Purohit T, Malik B, Zhao T, Wang J, 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 and Grembecka J.(2015). Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell, 13;27(4):589-602

Highlighted by:

12. Tomasz Cierpicki and Jolanta Grembecka. (2015) Targeting protein–protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies? Immunological Reviews, 263(1):279-301

11.Lund G, Dudkin S, Borkin D, Ni W, Grembecka J, Cierpicki T. (2014) Inhibition of CDC25B Phosphatase Through Disruption of Protein-Protein Interaction. ACS Chem Biol.  10(2):390-4

10. Murai MJ, Pollock J, He S, Miao H, Purohit T, Yokom A, Hess JL, Muntean AG, Grembecka J, Cierpicki T. (2014) The same site on LEDGF IBD domain represents therapeutic target for MLL leukemia and HIV. Blood.  124(25):3730-7

9. Lund G and Cierpicki T. (2014) Solution NMR studies reveal no global flexibility in the catalytic domain of CDC25B. ProteinsNov; 82(11): 2889-95

8.  Cierpicki T and Grembecka J. (2014) Challenges and opportunities in targeting the menin- MLL interaction. Future Med Chem6(4):447-62

7. Grembecka J, He S, Senter TJ, Pollock J, Han C, Upadhyay SK, Purohit T, Gogliotti RD, Lindsley CW, Cierpicki T, Stauffer SR. (2014) High-affinity small molecule inhibitors of the menin-Mixed Lineage Leukemia (MLL) interaction closely mimic a natural protein-protein interaction. J Med Chem. 57(4):1543-56

6. Manka J, Daniels RN, Dawson E, Daniels JS, Southall N, Jadhav A, Zheng W, Austin C, Grembecka J, Cierpicki T, Lindsley CW, Stauffer SR. (2013) Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction. Probe Reports from the NIH Molecular Libraries Program. Bethesda (MD): National Center for Biotechnology Information (US); 2010-2011

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. This publication was highlighted in Nat Rev Cancer. 2012, 12 (3):154 and Nat Rev Drug
Discov.
2012, 11(3):190.

Highly cited paper by Web of Science

4. Shi A, Murai MJ, He S, Lund G, Hartley T, Purohit T, Reddy G, Chruszcz M, Grembecka J and Cierpicki T. (2012) Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood.120, 4461 This article has been selected as plenary paper and featured on the cover of Blood

3. Gray FL, Murai MJ, Grembecka J, Cierpicki T. (2012) Detection of disordered regions in globular proteins using (13) C-detected NMR. Protein Science. 21, 1954

2. Murai MJ, Chruszcz M, Reddy G, Grembecka J, Cierpicki T. (2011). Crystal structure of Menin reveals the binding site for mixed lineage Leukemia (MLL) protein. J Biol Chem. 286, 31742-8.

1. Grembecka J, Belcher AM, Hartley T, Cierpicki T. (2010) Molecular basis of the Mixed Lineage Leukemia (MLL) - menin interaction: implications for targeting MLL leukemias, J. Biol. Chem. 285:40690.

 

 

Collaborative publications

28. Henderson AR, Henley MJ, Foster NJ, Peiffer AL, Beyersdorf MS, Stanford KD, Sturlis SM, Linhares BM, Hill ZB, Wells JA, Cierpicki T, Brooks CL 3rd, Fierke CA, Mapp AK. (2018) Conservation of coactivator engagement mechanism enables small-molecule allosteric modulators. Proc Natl Acad Sci U S A.  115(36):8960-8965

27. Wang Q, Yan R, Pinnell N, McCarter AC, Oh Y, Liu Y, Sha C, Garber NF, Chen Y, Wu Q, Ku CJ, Tran I, Serna Alarcon A, Kuick R, Engel JD, Maillard I, Cierpicki T, Chiang MY. (2018) Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development. Blood, in press

26. Svoboda LK, Teh SSK, Sud S, Kerk S, Zebolsky A, Treichel S, Thomas D, Halbrook CJ, Lee HJ, Kremer D, Zhang L, Klossowski S, Bankhead AR, Magnuson B, Ljungman M, Cierpicki T, Grembecka J, Lyssiotis CA, Lawlor ER. (2018). Menin regulates the serine biosynthetic pathway in Ewing sarcoma. J Pathol. 245(3):324-336.

25Jedwabny W, Kłossowski S, Purohit T, Cierpicki T, Grembecka J, Dyguda-Kazimierowicz E. (2018) Theoretical models of inhibitory activity for inhibitors of protein-protein interactions: targeting menin-mixed lineage leukemia with small molecules. Medchemcomm. 8(12):2216-2227.

24. Serio J, Ropa J, Chen W, Mysliwski M, Saha N, Chen L, Wang J, Miao H, Cierpicki T, Grembecka J, Muntean AG. (2018) The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia. Oncogene ;37(4):450-460.

23Sundaresan S, Meininger CA, Kang AJ, Photenhauer AL, Hayes MM, Sahoo N, Grembecka J, Cierpicki T, Ding L, Giordano TJ, Else T, Madrigal DJ, Low MJ, Campbell F, Baker AM, Xu H, Wright NA, Merchant JL. (2017). Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells. Gastroenterology. 153(6):1555-1567

22Oo ZM, Illendula A, Grembecka J, Schmidt C, Zhou Y, Esain V, Kwan W, Frost I, North TE, Rajewski RA, Speck NA, Bushweller JH. (2017). A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFβ in leukemic cells. Leuk Lymphoma. 1-13

21. Svoboda LK, Bailey N, Van Noord RA, Krook MA, Harris A, Cramer C, Jasman B, Patel RM, Thomas D, Borkin D, Cierpicki T, Grembecka J, Lawlor ER. (2017). Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL1 and menin. Oncotarget. 8(1):458-471

20. Carpenter C, Sorenson RJ, Jin Y, Klossowski S, Cierpicki T, Gnegy M, Showalter HD. (2016) Design and synthesis of triarylacrylonitrile analogues of tamoxifen with improved binding selectivity to protein kinase C. Bioorg Med Chem. 24(21):5495-5504.

19. Illendula A, Gilmour J, Grembecka J, Tirumala VS, Boulton A, Kuntimaddi A, Schmidt C, Wang L, Pulikkan JA, Zong H, Parlak M, Kuscu C, Pickin A, Zhou Y, Gao Y, Mishra L, Adli M, Castilla LH, Rajewski RA, Janes KA, Guzman ML, Bonifer C, Bushweller JH. (2016) Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers. EBioMedicine. 8:117-31.

18. Cardenas MG, Yu W, Beguelin W, Teater MR, Geng H, Goldstein RL, Oswald E, Hatzi K, Yang SN, Cohen J, Shaknovich R, Vanommeslaeghe K, Cheng H, Liang D, Cho HJ, Abbott J, Tam W, Du W, Leonard JP, Elemento O, Cerchietti L, Cierpicki T, Xue F, MacKerell AD Jr, Melnick AM. (2016). Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma. J Clin Invest. 126(9):3351-62

17. Nancy Pinnell, Ran Yan, Hyo Je Cho, Theresa Keeley, Marcelo J. Murai, Yiran Liu, Amparo Serna Alarcon, Jason Qin, Qing Wang, Rork Kuick, Kojo S.J. Elenitoba-Johnson, Ivan Maillard, Linda C. Samuelson, Tomasz Cierpicki, Mark Y. Chiang. (2015). The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia. Immunity 43(5):870-83

16. Schaller M, Ito T, Allen RM, Kroetz D, Kittan N, Ptaschinski C, Cavassani K, Carson WF 4th, Godessart N, Grembecka J, Cierpicki T, Dou Y, Kunkel SL. Epigenetic regulation of IL-12-dependent T cell proliferation. (2015). J Leukoc Biol. 98(4):601-13.

15. Senter T, Gogliotti RD, Han C, Locuson CW, Morrison R, Daniels JS, Cierpicki T, Grembecka JLindsley CW, Stauffer SR. Progress towards small molecule menin-mixed lineage leukemia (MLL) interaction inhibitors with in vivo utility. (2015). Bioorg Med Chem Lett.25(13):2720-5.

14. Jones M, Chase J, Brinkmeier M, Xu J, Weinberg DN, Schira J, Friedman A, Malek S, Grembecka J, Cierpicki T, Dou Y, Camper SA, Maillard I. (2015) Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells. J Clin. Invest., 125(5):2007-20

 

13. Malik R, Khan AP, Asangani IA, CieÅ›lik M, Prensner JR, Wang X, Iyer MK, Jiang X, Borkin D, Escara-Wilke J, Stender R, Wu YM, Niknafs YS, Jing X, Qiao Y, Palanisamy N, Kunju LP, Krishnamurthy PM, Yocum AK, Mellacheruvu D, Nesvizhskii AI, Cao X, Dhanasekaran SM,

Feng FY, Grembecka J, Cierpicki T, Chinnaiyan AM. (2015) Targeting the MLL complex in castration-resistant prostate cancer.  Nature Medicine. 21(4):344-52

 

12Anuradha Illendula, John A. Pulikkan, Hongliang Zong, Jolanta Grembecka, Liting Xue, Siddhartha Sen, Yunpeng Zhou, Adam Boulton, Aravinda Kuntimaddi, Yan Gao, Roger A. Rajewski, Monica L. Guzman, Lucio H. Castilla and John H. Bushweller. (2015) A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science347 (6223): 779-784

11.Abulwerdi FA, Liao C, mady AS, Gavin J, Shen C, Cierpicki T, Stuckey JA,Showalter HD, Nikolovska-Coleska Z. (2014) 2-Substituted-N-(4-hydroxynaphthalen-1-yl)arylsulfonamides as a novel class of selective Mcl-1 inhibitors: structure-based design, synthesis, SAR,

and biological evaluation. J Med Chem. 57(10):4111-33 http://pubs.acs.org/doi/abs/10.1021/jm500010b

10. Larsen MJ, Larsen SD, Fribley A, Grembecka J, Homan K, Mapp A Haak A, Nikolovska-Coleska Z, Stuckey JA, Sun D, Sherman DH. (2014) The role of HTS in drug discovery at the University of Michigan. Comb Chem High Throughput Screen. 17(3):210-30

http://www.eurekaselect.com/119515/article

9. Mitra P, Shultis D, Brender JR, Czajka J, Marsh D, Gray F, Cierpicki T, Zhang Y. (2013) An evolution-based approach to De Novo protein design and case study on Mycobacterium tuberculosis. PLoS Comput Biol. 9(10):e1003298.

http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1003298

8. Kittan NA, Allen RM, Dhaliwal A, Cavassani KA, Schaller M, Gallagher KA, Carson WF 4th, Mukherjee S, Grembecka J, Cierpicki T, Jarai G, Westwick J, Kunkel SL, Hogaboam CM. (2013) Cytokine induced phenotypic and epigenetic signatures are key to
establishing specific macrophage phenotypes. PLoS One. 8(10):e78045.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0078045

7. Sio A, Chehal MK, Tsai K, Fan X, Roberts ME, Nelson BH, Grembecka J, Cierpicki T, Krebs DL, Harder KW. (2013) Dysregulated Hematopoiesis Caused by Mammary Cancer Is Associated with Epigenetic Changes and Hox Gene Expression in
Hematopoietic Cells. Cancer Res. 73(19):5892-904

http://cancerres.aacrjournals.org/content/73/19/5892.long

6. Abulwerdi F, Liao C, Liu M, Azmi AS, Aboukameel A, Mady AS, Gulappa T, Cierpicki T, Owens S, Zhang T, Sun D, Stuckey JA, Mohammad RM, Nikolovska-Coleska Z. (2013) A Novel Small-Molecule Inhibitor of Mcl-1 Blocks Pancreatic Cancer Growth In
vitro and In vivo. Mol Cancer Ther. in press 

http://mct.aacrjournals.org/content/early/2013/09/07/1535-7163.MCT-12-0767.long

5. Rakowski LA, Garagiola DD, Li CM, Decker M, Caruso S, Jones M, Kuick R, Cierpicki T, Maillard I, Chiang MY. (2013). Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias. Cancer Res. 73(2):930-41

http://cancerres.aacrjournals.org/content/73/2/930.long

4. Majmudar CY, Højfeldt JW, Arevang CJ, Pomerantz WC, Gagnon JK, Schultz PJ, Cesa LC, Doss CH, Rowe SP, Vásquez V, Tamayo-Castillo G, Cierpicki T, Brooks CL 3rd, Sherman DH, Mapp AK. (2012). Sekikaic Acid and Lobaric Acid Target a Dynamic
Interface of the Coactivator CBP/p300. Angew Chem Int Ed Engl. 51, 11258

http://onlinelibrary.wiley.com/doi/10.1002/anie.201206815/abstract

3. Pomerantz WC, Wang N, Lipinski AK, Wang R, Cierpicki T, Mapp AK. (2012) Profiling the Dynamic Interfaces of Fluorinated Transcription Complexes for Ligand Discovery and Characterization. ACS Chem Biol. 2012 Jul 2

http://pubs.acs.org/doi/abs/10.1021/cb3002733

2. Gill SK, Xu H, Kirchhoff PD, Cierpicki T, Turbiak AJ, Wan B, Zhang N, Peng KW, Franzblau SG, Garcia GA, Showalter HD. (2012) Structure-based design of novel benzoxazinorifamycins with potent binding affinity to wild-type and rifampin-resistant mutant Mycobacterium tuberculosis RNA polymerases. J Med Chem. Apr 26;55(8):3814-26

http://pubs.acs.org/doi/abs/10.1021/jm201716n

1. Cao F, Chen Y, Cierpicki T, Liu Y, Basrur V, Lei M, Dou Y. (2010). An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain. PLoS One 5:14102.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0014102