Impact

Chemical Probes for Epigenetics

Potent, selective and cell-permeable inhibitors of protein function ("chemical probes") are valued reagents in both fundamental and applied biological research, yet rarely available.

Chemical probes are essential for the early stages of drug discovery by allowing preclinical target validation in both academic and industrial laboratories: well-characterised inhibitors with defined mechanisms of action are important drivers of industrial drug discovery programmes.

Since 2008 the SGC has led an initiative to develop chemical probes that can selectively stimulate or block the activity of proteins involved in epigenetic control, complementing genetic knockouts and RNAi approaches to understand the cellular role of these proteins.

• Continual generation of high-quality, open access chemical probes for epigenetics proteins (in excess of 14 probes, as of July 2013).

  • G9a methyltransferase (UNC0638 Nature Chemical Biology, 2011, UNC0642) 

  • BET/ BRD4 (JQ1, Nature 2010)

  • BET (PFI-1, Cancer Research 2013 )

  • EZH2/1 (GSK343/UNC1999, ACS Med Chem Letters 2012 )

  • Lysine Demethylase/ JMJD3 & UTX (GSK-J1,  Nature 2012)

  • See the full list of SGC Epigenetics probes

Target Characterization

In coordination with GSK (Nature. 2010 Dec 23;468(7327):1119-23. doi: 10.1038/nature09589), identified the potential of Brd4 as a drug discovery target (Filippakopoulos et al, Nature 2010). With the Frye laboratory, found that methyl-lysine binding proteins can be targeted with small-molecules; possible relevance to reprogramming and regenerative medicine (Herold et al, J.Med.Chem 2011). Cofactor pocket of Histone Methyl Transferases is druggable and structurally diverse (Campagne-Slater et al, J Chem Inf Model 2011). Helped GSK to identify the potential of histone demethylase JMJD3 as a drug discovery target in inflammation (Kruidenier et al,  Nature 2012). Worked with scientists at Pfizer and at UBC to show that SETD7 is involved in the control of cell size (submitted)

Structures

Deposited more than 1500 high-resolution structures of medically relevant human and parasite proteins into the public databases Solved the structure of the first human ABC transporter: the mitochondrial ABC transporter ABCB10 (PDB ID 2YL4) and the first structure of human ZMPSTE24, a nuclear zinc metalloprotease involved in laminopathies, which includes progeria (PDB ID 4AW6, 2YPT; read more about it ) Structural and functional characterization of ERAP1 protease (PDB ID: 3QNF; Kochan et al, PNAS 2011) and TNIK (PDB ID: 2X7F, GWAS-linked targets for ankylosing spondylitis and schizophrenia respectively. 3D structures of more than 75 novel human protein kinases (of which 63 were releases for the first time in the public domain), including medically important human protein kinases such as PHKG2, LIMK1 and ACVR2.

Recombinant Antibodies

• Helped coordinate Renewable Protein Binding Working Group (incorporating more than 11 institutions worldwide) that produced hundreds of antibodies targeting 20 SH2 domain proteins (Colwill et al, Nature Methods 2011).
• Launched a project to develop technologies, libraries and recombinant antibodies to human epigenetic proteins. The project is a carried out in partnership with several of the world leaders in the field (Sidhu, Kossiakoff, Dübel, Koide) and all output is to be made available without restriction on use.
• Generated single digit nM recombinant antibody and antibody-like reagents to over 100 human proteins.