A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1

We report the design and characterization of UNC3866, a potent antagonist of the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently, with a K d of â ∼1/4100 nM for each, and is 6-to 18-fold selective as compared to seven other CBX and CDY chromodomains while being highly selective over >250 other protein targets. X-ray crystallography revealed that UNC3866's interactions with the CBX chromodomains closely mimic those of the methylated H3 tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage, whereas UNC4219, a methylated negative control compound, has negligible effects

Erratum: Addendum: A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1 (Nature chemical biology (2016) 12 3 (180-187))

[No abstract available

Toward target 2035: EUbOPEN: a public-private partnership to enable & unlock biology in the open

Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public–private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents. The substantial outputs of this programme include a chemogenomic compound library covering one third of the druggable proteome, as well as 100 chemical probes, both profiled in patient derived assays, as well as hundreds of data sets deposited in existing public data repositories and a project-specific data resource for exploring EUbOPEN outputs. Chemical Immunolog

Investigating the record of Permian climate change from argillaceous sedimentary rocks, Oman

A standard method for the analysis of carbon isotope composition of bulk organic matter (δ13Cbulk) in palaeoenvironmental and stratigraphic studies of sedimentary basins associated with hydrocarbons is suggested. This method includes the removal of interstitial hydrocarbon within the sediments, which is shown to have a negative effect on δ13C. Using the method, a δ13Cbulk trend (c. −21 to −24‰) was found within the Lower Permian Al Khlata and lower Gharif formations of Thuleilat-16 and -42 well sections, south Oman. Palaeontological and sedimentological evidence indicates considerable palaeoenvironmental change, from a cold climate lowland fern flora and upland primitive conifer flora low in the sequence, to a lowland cycad-like and upland glossopterid or other gymnospermous flora higher in the sequence. The lithologies range from glacial diamictite at the base to calcrete horizons and redbeds at the top. It is therefore likely that the δ13Cbulk trend is related to palaeoenvironmental change