The bromodomain and extra C-terminal domain (BET) family of proteins are epigenetic regulators - termed ‘readers’ - that bind to the acetylated lysine residues of histones and recruit a variety of important co-factors for gene transcription. The BET protein, BRD4, has emerged as an exciting target for cancer therapeutics because of its role in mediating the transcription of notorious oncogene c-MYC.
A number of small molecule inhibitors of BRD4 are known. However, many of them also display similar binding affinities to related BETs such as BRD2, BRD3 and BRDT.[1] Since BRD2 disruption has been shown to cause obesity in mice,[2] Brd3 is involved in erythroid maturation[3] and BRDT is responsible for chromatin remodeling during spermatogenesis,[4] the therapeutic potential of compounds that also affect these BETs is limited. This poster will discuss our studies towards the development of selective inhibitors of BETs based on novel heterocyclic acetyl-lysine mimetics using a medicinal chemistry approach.
[1] Hewings, D. S., Rooney,T.P.C., Jennings, L. E., Hay, D. A., Schofield, C. J., Brennan, P. E., Knapp, S., Conway, S. J., J. Med. Chem., (2012), 55, 9393.
[2] Wang, F., Liu, H., Blanton, W. P., Belkina, A., Lebrasseur, N. K., Denis, G. V., Biochem. J., (2010) 425, 71.
[3] Lamonica, J. M., Deng, W., Kadauke, S., Cambell, A. E., Gamsjaeger, R., Wand, H., Cheng, Y., Billin, A. N., Hardison, R. C., Mackay, J. P., Blobel, G. A., PNAS, (2011), 22, 8927.
[4] Matzuk, M. M., McKeown, M. R., Filippakopoulos, P., Li, Q., Ma, L., Agno, J. E., Lemieux, M. E., Picaud, S., Yu, R. N., Qi, J., Knapp, S., Bradner, J. E., Cell, (2012), 150, 673.