TY - JOUR
T1 - A chemical biology toolbox to study protein methyltransferases and epigenetic signaling
AU - Scheer, Sebastian
AU - Ackloo, Suzanne
AU - Medina, Tiago S.
AU - Schapira, Matthieu
AU - Li, Fengling
AU - Ward, Jennifer A.
AU - Lewis, Andrew M.
AU - Northrop, Jeffrey P.
AU - Richardson, Paul L.
AU - Kaniskan, H. Ümit
AU - Shen, Yudao
AU - Liu, Jing
AU - Smil, David
AU - McLeod, David
AU - Zepeda-Velazquez, Carlos A.
AU - Luo, Minkui
AU - Jin, Jian
AU - Barsyte-Lovejoy, Dalia
AU - Huber, Kilian V.M.
AU - De Carvalho, Daniel D.
AU - Vedadi, Masoud
AU - Zaph, Colby
AU - Brown, Peter J.
AU - Arrowsmith, Cheryl H.
N1 - Funding Information:
We thank our numerous medicinal chemistry collaborators in the pharmaceutical industry, the Ontario Institute for Cancer Research (OICR), and the Jin, Frye, and Luo Labs who helped develop probes in this resource. Michael Curtin and Hongyu Zhou (Abbvie) contributed to the development of (A-395)-NH2 and (A-395)-biotin. Stefan Gradl and Carlo Stresemann (Bayer) spearheaded the discovery of BAY-6035. Kazuhide Nakayama (Takeda) contributed to the development of TP-064. Hiroshi Nara and Nozomu Sakai (Takeda) contributed to the discovery of SGC3027. 7TM, kinase, and ion channel off-target selectivity screening was kindly supplied by Eurofins-Cerep. Additional Ki determinations and receptor binding profiles were generously provided by the National Institute of Mental Health’s (NIMH) Psychoactive Drug Screening Program, (Contract # HHSN-271-2013-00017-C) directed by B.L. Roth, University of North Carolina at Chapel Hill and Project Officer J. Driscoll at NIMH, Bethesda, Maryland, USA. We thank B. Kessler, S. Bonham and R. Fischer from the TDI Discovery Proteomics Facility, Oxford University, for their support. We acknowledge Mark Silverberg, Michelle Smith, Beatrice Luu and Grace Chan from Mount Sinai Hospital (Canada) for their contribution in the collection of human blood samples used in this study. This work was supported by the Canadian Institutes of Health Research [FDN-154328 and 128090 to C.H.A., and FDN-148430 and 201512MSH-360794-228629 to D.D.C.], Canadian Cancer Society [CCSRI 703716 to D.D.C.], the Australian National Health and Medical Research Council (project grants 1104433 and 1104466 to C.Z.), Myeloma UK [J.A.W., A.M.L., and K.V.M.H.], the U.S. National Institutes of Health [R01GM122749, R01CA218600, and R01HD088626 to J.J.], the OICR Drug Discovery Program (funded by the government of Ontario), and the Structural Genomics Consortium (SGC) which is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute [OGI-055], Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA, Darmstadt, Germany, MSD, Novartis Pharma AG, Ontario Ministry of Research, Innovation and Science (MRIS), Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and Wellcome. T.M. is supported by a fellowship "Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)", Brazil. C.Z. is a VESKI Innovation Fellow.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4 + T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond.
AB - Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4 + T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond.
UR - http://www.scopus.com/inward/record.url?scp=85059495359&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-07905-4
DO - 10.1038/s41467-018-07905-4
M3 - Article
C2 - 30604761
AN - SCOPUS:85059495359
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 19
ER -