YX968

YX968 : Degrader (PROTAC) of HDAC3, HDAC8

Structure

SERP Rating

In Cells

(4 ratings)

In Model Organisms

(0 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

HDAC3
HDAC8

Degrader (PROTAC)

100 nM

Probe Availability:

ProbeChem

In Vitro Validations

Uniprot ID: O15379

Target Class: Epigenetic

Target SubClass: HDAC

Potency: IC50

Potency Value: 283.8 ± 50.6 nM

Potency Assay: HDAC activity assays

PDB ID for probe-target interaction (3D structure): --

Target aliases:

Histone deacetylase 3, HDAC3, HDAC3_HUMAN, HD3, SM ...

DOI Reference: 10.1016/j.chembiol.2023.07.010

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay, off target (cells): Tandem Mass Tag (TMT)-based quantitative proteomic profiling experiment was used to assess selectivity: samples were prepared by treating MDA-MB-231 cells with either YX968 (100 nM) or DMSO for 2 h. Of >7000 screened proteins, it did not detect any other significantly downregulated protein (log2FC < −1 and p < 0.01) except for HDAC8 and NCOR1. YX968 potently degraded HDAC3, but did not affect HDAC1 or HDAC2, in either MCF7 (an estrogen receptor [ER]-positive BC cell line) or MDA-MB-231 treated for 8 h with concentrations of up to 1µM.

Potency assay (off target): HDAC1 IC50 591.0 ± 87.5 nM enzymatic assay

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

YX968 is a well characterized PROTAC with excellent selectivity for its two targets (HDAC3 and HDAC8), demonstrated with classical Western Blotting techniques as well as unbiased proteomics analysis. As YX968 has similar DC50 values for HDAC3 (1.7 nM; MDA-MB-231 cells) and HDAC8 (6.1 nM; MDA-MB-231 cells), it is not appropriate for use in studying the function of either protein individually; however, it is an excellent chemical probe for studying the two proteins simultaneously.

(last updated: 26 Oct 2023 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

Broader in cell selectivity data and proof of HDAC3 engagement data is needed.

(last updated: 31 Oct 2024 )

SERP+ Ratings

In Cell Rating

(last updated: 31 Oct 2024 )

SERP Ratings

In Cell Rating

SERP Comments:

A useful probe for interrogating the effect of combined degradation of HDAC3 and -8. It may be worth considering the degradation of the off-targets NCOR1 and EPHX2.

(last updated: 20 Feb 2025 )