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10. Menin in complex with MI-853

Author

Borkin, D., primary, Klossowski, S., additional, Pollock, J., additional, Linhares, B., additional, Cierpicki, T., additional, and Grembecka, J., additional

Published
2018
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11. Menin in complex with MI-1482

Author

Borkin, T., primary, Klossowski, S., additional, Pollock, J., additional, Linhares, B., additional, Cierpicki, T., additional, and Grembecka, J., additional

Published
2018
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12. Menin in complex with MI-1481

Author

Borkin, D., primary, Klossowski, S., additional, Pollock, J., additional, Linhares, B., additional, Cierpicki, T., additional, and Grembecka, J., additional

Published
2018
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16. Discovery of novel menin-MLL small molecule inhibitors that display high potency and selectivity in vitro and in vivo

Author

Kessler, L., primary, Wu, T., additional, Grembecka, J., additional, Cierpicki, T., additional, Purohit, T., additional, Miao, H., additional, Kempinska, K., additional, Ely, T., additional, Hensen, R., additional, Li, S., additional, Patricelli, M., additional, Kucharski, J., additional, Zhang, J., additional, Yao, Y., additional, Yu, K., additional, Wang, Y., additional, Li, L., additional, Ren, P., additional, and Liu, Y., additional

Published
2016
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28. Menin-MLL inhibitors block oncogenic transformation by MLL-fusion proteins in a fusion partner-independent manner

Author

He, S, primary, Malik, B, additional, Borkin, D, additional, Miao, H, additional, Shukla, S, additional, Kempinska, K, additional, Purohit, T, additional, Wang, J, additional, Chen, L, additional, Parkin, B, additional, Malek, S N, additional, Danet-Desnoyers, G, additional, Muntean, A G, additional, Cierpicki, T, additional, and Grembecka, J, additional

Published
2015
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33. Characterization of the Plasmodium falciparum M17 leucyl aminopeptidase: A protease involved in amino acid regulation with potential for antimalarial drug development

Author

Stack, CM, Lowther, J, Cunningham, E, Donnelly, S, Gardiner, DL, Trenholme, KR, Skinner-Adams, TS, Teuscher, F, Grembecka, J, Mucha, A, Kafarski, P, Lua, L, Bell, A, and Dalton, JP

Subjects
Ions, Biochemistry & Molecular Biology, Merozoites, Plasmodium falciparum, Hydrogen-Ion Concentration, Immunohistochemistry, Recombinant Proteins, Leucyl Aminopeptidase, Antimalarials, Kinetics, Cytosol, Leucine, Animals, Trophozoites, Amino Acids, Phylogeny, Plasmids
Abstract

Amino acids generated from the catabolism of hemoglobin by intra-erythrocytic malaria parasites are not only essential for protein synthesis but also function in maintaining an osmotically stable environment, and creating a gradient by which amino acids that are rare or not present in hemoglobin are drawn into the parasite from host serum. We have proposed that a Plasmodium falciparum M17 leucyl aminopeptidase (PfLAP) generates and regulates the internal pool of free amino acids and therefore represents a target for novel antimalarial drugs. This enzyme has been expressed in insect cells as a functional 320-kDa homo-hexamer that is optimally active at neutral or alkaline pH, is dependent on metal ions for activity, and exhibits a substrate preference for N-terminally exposed hydrophobic amino acids, particularly leucine. PfLAP is produced by all stages in the intra-erythrocytic developmental cycle of malaria but was most highly expressed by trophozoites, a stage at which hemoglobin degradation and parasite protein synthesis are elevated. The enzyme was located by immunohistochemical methods and by transfecting malaria cells with a PfLAP-green fluorescent protein construct, to the cytosolic compartment of the cell at all developmental stages, including segregated merozoites. Amino acid dipeptide analogs, such as bestatin and its derivatives, are potent inhibitors of the protease and also block the growth of P. falciparum malaria parasites in culture. This study provides a biochemical basis for the antimalarial activity of aminopeptidase inhibitors. Availability of functionally active recombinant PfLAP, coupled with a simple enzymatic readout, will aid medicinal chemistry and/or high throughput approaches for the future design/discovery of new antimalarial drugs. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Published
2007

34. A synthetic method for diversification of the P1′ substituent in phosphinic dipeptides as a tool for exploration of the specificity of the S1′ binding pockets of leucine aminopeptidases

Author

Vassiliou, S. Xeilari, M. Yiotakis, A. Grembecka, J. Pawełczak, M. Kafarski, P. Mucha, A.

Abstract

A novel, general, and versatile method of diversification of the P1′ position in phosphinic pseudodipeptides, presumable inhibitors of proteolytic enzymes, was elaborated. The procedure was based on parallel derivatization of the amino group in the suitably protected phosphinate building blocks with appropriate alkyl and aryl halides. This synthetic strategy represents an original approach to phosphinic dipeptide chemistry. Its usefulness was confirmed by obtaining a series of P1′ modified phosphinic dipeptides, inhibitors of cytosolic leucine aminopeptidase, through computer-aided design basing on the structure of homophenylalanyl-phenylalanine analogue (hPheP[CH2]Phe) bound in the enzyme active site as a lead structure. In this approach novel interactions between inhibitor P1′ fragment and the S1′ region of the enzyme, particularly hydrogen bonding involving Asn330 and Asp332 enzyme residues, were predicted. The details of the design, synthesis, and activity evaluation toward cytosolic leucine aminopeptidase and aminopeptidase N are discussed. Although the potency of the lead compound has not been improved, marked selectivity of the synthesized inhibitors toward both studied enzymes was observed. © 2007 Elsevier Ltd. All rights reserved.

Published
2007

35. Human menin with bound inhibitor MIV-5

Author

He, S., primary, Senter, T.J., additional, Pollock, J.W., additional, Han, C., additional, Upadhyay, S.K., additional, Purohit, T., additional, Gogliotti, R.D., additional, Lindsley, C.W., additional, Cierpicki, T., additional, Stauffer, S.R., additional, and Grembecka, J., additional

Published
2014
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36. Human menin with bound inhibitor MIV-3R

Author

He, S., primary, Senter, T.J., additional, Pollock, J.W., additional, Han, C., additional, Upadhyay, S.K., additional, Purohit, T., additional, Gogliotti, R.D., additional, Lindsley, C.W., additional, Cierpicki, T., additional, Stauffer, S.R., additional, and Grembecka, J., additional

Published
2014
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37. Human menin with bound inhibitor MIV-4

Author

He, S., primary, Senter, T.J., additional, Pollock, J.W., additional, Han, C., additional, Upadhyay, S.K., additional, Purohit, T., additional, Gogliotti, R.D., additional, Lindsley, C.W., additional, Cierpicki, T., additional, Stauffer, S.R., additional, and Grembecka, J., additional

Published
2014
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38. Human menin with bound inhibitor MIV-6R

Author

He, S., primary, Senter, T.J., additional, Pollock, J.W., additional, Han, C., additional, Upadhyay, S.K., additional, Purohit, T., additional, Gogliotti, R.D., additional, Lindsley, C.W., additional, Cierpicki, T., additional, Stauffer, S.R., additional, and Grembecka, J., additional

Published
2014
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39. Human menin with bound inhibitor MIV-7

Author

He, S., primary, Senter, T.J., additional, Pollock, J.W., additional, Han, C., additional, Upadhyay, S.K., additional, Purohit, T., additional, Gogliotti, R.D., additional, Lindsley, C.W., additional, Cierpicki, T., additional, Stauffer, S.R., additional, and Grembecka, J., additional

Published
2014
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41. The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia

Author

Serio, J, Ropa, J, Chen, W, Mysliwski, M, Saha, N, Chen, L, Wang, J, Miao, H, Cierpicki, T, Grembecka, J, and Muntean, A G

Abstract

Acute myeloid leukemia (AML) is a disease associated with epigenetic dysregulation. 11q23 translocations involving the H3K4 methyltransferase MLL1 (KMT2A) generate oncogenic fusion proteins with deregulated transcriptional potential. The polymerase-associated factor complex (PAFc) is an epigenetic co-activator complex that makes direct contact with MLL fusion proteins and is involved in AML, however, its functions are not well understood. Here, we explored the transcriptional targets regulated by the PAFc that facilitate leukemia by performing RNA-sequencing after conditional loss of the PAFc subunit Cdc73. We found Cdc73 promotes expression of an early hematopoietic progenitor gene program that prevents differentiation. Among the target genes, we confirmed the protein arginine methyltransferase Prmt5 is a direct target that is positively regulated by a transcriptional unit that includes the PAFc, MLL1, HOXA9 and STAT5 in leukemic cells. We observed reduced PRMT5-mediated H4R3me2s following excision of Cdc73 placing this histone modification downstream of the PAFc and revealing a novel mechanism between the PAFc and Prmt5. Knockdown or pharmacologic inhibition of Prmt5 causes a G1 arrest and reduced proliferation resulting in extended leukemic disease latency in vivo. Overall, we demonstrate the PAFc regulates Prmt5 to facilitate leukemic progression and is a potential therapeutic target for AMLs.

Published
2018
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42. Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases

Author

McGowan, S, Oellig, CA, Birru, WA, Caradoc-Davies, TT, Stack, CM, Lowther, J, Skinner-Adams, T, Mucha, A, Kafarski, P, Grembecka, J, Trenholme, KR, Buckle, AM, Gardiner, DL, Dalton, JP, Whisstock, JC, McGowan, S, Oellig, CA, Birru, WA, Caradoc-Davies, TT, Stack, CM, Lowther, J, Skinner-Adams, T, Mucha, A, Kafarski, P, Grembecka, J, Trenholme, KR, Buckle, AM, Gardiner, DL, Dalton, JP, and Whisstock, JC

Abstract

Current therapeutics and prophylactics for malaria are under severe challenge as a result of the rapid emergence of drug-resistant parasites. The human malaria parasite Plasmodium falciparum expresses two neutral aminopeptidases, PfA-M1 and PfA-M17, which function in regulating the intracellular pool of amino acids required for growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. We previously reported the x-ray crystal structure of the monomeric PfA-M1 and proposed a mechanism for substrate entry and free amino acid release from the active site. Here, we present the x-ray crystal structure of the hexameric leucine aminopeptidase, PfA-M17, alone and in complex with two inhibitors with antimalarial activity. The six active sites of the PfA-M17 hexamer are arranged in a disc-like fashion so that they are orientated inwards to form a central catalytic cavity; flexible loops that sit at each of the six entrances to the catalytic cavern function to regulate substrate access. In stark contrast to PfA-M1, PfA-M17 has a narrow and hydrophobic primary specificity pocket which accounts for its highly restricted substrate specificity. We also explicate the essential roles for the metal-binding centers in these enzymes (two in PfA-M17 and one in PfA-M1) in both substrate and drug binding. Our detailed understanding of the PfA-M1 and PfA-M17 active sites now permits a rational approach in the development of a unique class of two-target and/or combination antimalarial therapy.

Published
2010

43. Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase

Author

McGowan, S, Porter, CJ, Lowther, J, Stack, CM, Golding, SJ, Skinner-Adams, TS, Trenholme, KR, Teuscher, F, Donnelly, SM, Grembecka, J, Mucha, A, Kafarski, P, Degori, R, Buckle, AM, Gardiner, DL, Whisstock, JC, Dalton, JP, McGowan, S, Porter, CJ, Lowther, J, Stack, CM, Golding, SJ, Skinner-Adams, TS, Trenholme, KR, Teuscher, F, Donnelly, SM, Grembecka, J, Mucha, A, Kafarski, P, Degori, R, Buckle, AM, Gardiner, DL, Whisstock, JC, and Dalton, JP

Abstract

Plasmodium falciparum parasites are responsible for the major global disease malaria, which results in > 2 million deaths each year. With the rise of drug-resistant malarial parasites, novel drug targets and lead compounds are urgently required for the development of new therapeutic strategies. Here, we address this important problem by targeting the malarial neutral aminopeptidases that are involved in the terminal stages of hemoglobin digestion and essential for the provision of amino acids used for parasite growth and development within the erythrocyte. We characterize the structure and substrate specificity of one such aminopeptidase, PfA-M1, a validated drug target. The X-ray crystal structure of PfA-M1 alone and in complex with the generic inhibitor, bestatin, and a phosphinate dipeptide analogue with potent in vitro and in vivo antimalarial activity, hPheP[CH 2]Phe, reveals features within the protease active site that are critical to its function as an aminopeptidase and can be exploited for drug development. These results set the groundwork for the development of antimalarial therapeutics that target the neutral aminopeptidases of the parasite. © 2009 by The National Academy of Sciences of the USA.

Published
2009

44. Human menin with bound inhibitor MI-2

Author

Shi, A., primary, Murai, M.J., additional, He, S., additional, Lund, G.L., additional, Hartley, T., additional, Purohit, T., additional, Reddy, G., additional, Chruszcz, M., additional, Grembecka, J., additional, and Cierpicki, T., additional

Published
2012
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45. Human menin with bound inhibitor MI-2-2

Author

Shi, A., primary, Murai, M.J., additional, He, S., additional, Lund, G.L., additional, Hartley, T., additional, Purohit, T., additional, Reddy, G., additional, Chruszcz, M., additional, Grembecka, J., additional, and Cierpicki, T., additional

Published
2012
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46. Human menin in complex with MLL peptide

Author

Shi, A., primary, Murai, M.J., additional, He, S., additional, Lund, G.L., additional, Hartley, T., additional, Purohit, T., additional, Reddy, G., additional, Chruszcz, M., additional, Grembecka, J., additional, and Cierpicki, T., additional

Published
2012
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50. R164N mutant of the RUNX1 Runt domain

Author

Grembecka, J., primary, Zhe, L., additional, Lukasik, S.M., additional, Liu, Y., additional, Bielnicka, I., additional, Bushweller, J.H., additional, and Speck, N.A., additional

Published
2007
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