TY - JOUR
T1 - Developing Spindlin1 small-molecule inhibitors by using protein microarrays
AU - Bae, Narkhyun
AU - Viviano, Monica
AU - Su, Xiaonan
AU - Lv, Jie
AU - Cheng, Donghang
AU - Sagum, Cari
AU - Castellano, Sabrina
AU - Bai, Xue
AU - Johnson, Claire
AU - Khalil, Mahmoud Ibrahim
AU - Shen, Jianjun
AU - Chen, Kaifu
AU - Li, Haitao
AU - Sbardella, Gianluca
AU - Bedford, Mark T.
N1 - Funding Information:
M.T.B. was supported by an NIH grant (DK062248) and a CPRIT grant (RP130432) for the protein array analysis. The deep sequencing was supported by a CPRIT grant (RP120348) to J.S. The Center for Cancer Epigenetics at MDACC also supported this study. G.S. was supported by grants from the Italian Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Progetti di Ricerca di Interesse Nazionale (PRIN 2012ZHN9YH), the Universita di Salerno (Italy) and the European Cooperation in Science and Technology (COST Action CM1406). H.L. was supported by grants from the Major State Basic Research Development Program in China (2015CB910503 and 2016YFA0500700) and the Tsinghua University Initiative Scientific Research Program. N.B. was supported by the Odyssey Fellowship Program at the University of Texas MD Anderson Cancer Center.
Publisher Copyright:
© Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor-domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of SPIN1 inhibitors with increased selectivity (EML631-633), which engage SPIN1 in cells, block its ability to 'read' H3K4me3 marks and inhibit its transcriptional-coactivator activity. Protein microarrays can thus be used as a platform to 'target-hop' and identify small molecules that bind and compete with domain-motif interactions.
AB - The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor-domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of SPIN1 inhibitors with increased selectivity (EML631-633), which engage SPIN1 in cells, block its ability to 'read' H3K4me3 marks and inhibit its transcriptional-coactivator activity. Protein microarrays can thus be used as a platform to 'target-hop' and identify small molecules that bind and compete with domain-motif interactions.
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U2 - 10.1038/nchembio.2377
DO - 10.1038/nchembio.2377
M3 - Article
C2 - 28504676
AN - SCOPUS:85021067771
SN - 1552-4450
VL - 13
SP - 750
EP - 756
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 7
ER -