UNC3866
UNC3866 : Antagonist of CBX7, CBX4
Structure
In Cells
In Model Organisms
SERP ratings and comments
SERP Ratings
SERP Comments:
The probe UNC3866 has been well characterized for its interaction with the desired target CBX7 using ITC, a biotinylated analog, and co-crystal stuctures to provide strong evidence of interactions. Cellular penetration is low (5% of external concentration), meaning high concentrations are needed. A closely related, inactive analog provides evidence that the probe's biological effects are target related. However, the probe is active against other members of the CBX chromodomains (equipotent at CDX4) and also CDY choromodomains so attributing effects to a specific interaction in cells is not possible. The probe has been assessed for pharmacokinetics in mice (IP injection) and shows evidence of moderate clearance that may allow for use in vivo. The high concentrations required for cellular assays would be difficult to achieve in vivo, but the authors propose to examine this possible use in the future.
(last updated: 23 Oct 2016 )
SERP Ratings
SERP Comments:
This probe is well-characterized and somewhat selective for CBX4 and CBX7 in biochemical assays, though it is only 6-fold less active against CBX6 and about 10-fold less active against CDYL1b and CDYL2. It also has low cell permeability, necessitating high concentrations to be used in cell assays. This means that any biological effects observed in cell assays can not be attributed solely to inhibition of CBX4 and CBX7.
(last updated: 12 Jan 2017 )
SERP Ratings
SERP Comments:
UNC3866 is a first in class inhibitor for CBX7 and CBX4, as well as other related family members. It's highly potent in vitro and represents a great advancement in the CBX protein biology field. The compound was shown to inhibit cell proliferation at 7.6 uM, and at 30 uM, to induce a cell senescence phenotype that was linked to the target by data published elsewhere. A biotinylated version of the compound can pull down the PRC1 complex components, an effect that is inhibited if the PC3 cells were incubated with 30 uM of UNC3866 for 24 h prior to lysis and pulldown. Data on the cellular compound pulldowns was focused on the known targets instead of a broader proteomic profiling of the targets bound to UNC3866. Additional data on UNC3866's effect on more specific cellular activity readout such as nanoBRET or ChIP would be very informative.
(last updated: 21 Jan 2017 )