ML323

Allosteric inhibitor of USP1, WDR48

Structure

Information

Protein target names: USP1, WDR48

Mechanism of action: Allosteric inhibitor

In Vitro Validations

Uniprot ID: O94782
Target Class: Other post-translational modification
Target SubClass: Deubiquitinase
Potency: IC 50
Potency Value: 76 nM
Potency Assay: USP1/UAF1 activity was monitored in a fluorometric ubiquitin−rhodamine110 assay. ML323 also showed IC50s of 174 nM and 820 nM in orthogonal gel-based assays using K63-linked diubiquitin (di-Ub) and monoubiquitinated PCNA (Ub-PCNA) as substrates, respectively.
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: Yes, see J. Med. Chem publication for details.
Target aliases:
Ubiquitin carboxyl-terminal hydrolase 1, USP1, UBP ...

DOI Reference: 10.1038/nchembio.1455

In Cell Validations

In Vivo Data

No in Vivo Validations

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SERP ratings and comments


SERP Ratings

In Cell Rating

Comments:

ML323 is a selective USP1/UAF1 inhibitor that has been shown to have good Caco-2 permeability and to be efficacious in cellular assays at ≥5 µM. A compound in the same series (compound 77 in J. Med. Chem., 2014, 8099-8110) can be used as an inactive control. ML323 was found to have rapid clearance and has not been proposed for use in vivo.

(last updated: 15 Jan 2017 )

SERP Ratings

In Cell Rating

Comments:

ML323 is an allosteric, selective inhibitor of the USP1/UAF1 complex (also called USP1/WDR48). Note that ML323 is much less effective in inhibiting USP1 alone in biochemical assays. The full implications or relevance of this differential activity in cells has not been explored.

(last updated: 16 Jan 2017 )

SERP Ratings

In Cell Rating

Comments:

ML-323 is a unique, cell-permeable and highly selective inhibitor of the USP1/UAF1 complex. A notable discordance between biochemical and cellular potency for ML-323 is observed, and should be further examined. Furthermore, a more direct, biophysical assessment of intracellular target engagement would be valuable to explore the mechanism of the observed IC50 offset.

(last updated: 22 Jan 2017 )