QC-01-175

QC-01-175 : Degrader (PROTAC) of MAPT

Structure

SERP Rating

In Cells

(3 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

MAPT

Degrader (PROTAC)

100 nM, up to 10 uM
Reviewer recommended concentration: 1 µM and 10 µM

Probe Availability:

MedKoo

In Vitro Validations

Uniprot ID: P10636

Target Class: Extracellular protein

Target SubClass: Microtubule Associated Protein

Potency Value: 1.2 µM

Potency Assay: BLI measuring the interaction with wild-type tau, or mutant tau: A152T (KD1.7 μM) and P301L (KD2.5 μM)

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

Target aliases:

Microtubule-associated protein tau, TAU, MTBT1, MA ...

DOI Reference: 10.7554/eLife.45457

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay, off target (cells): Multiplexed MS-based proteomics was employed to identify potential off-targets of the QC-01–175 degrader in the A152T neuronal proteome, following a 4 hr treatment. Upon 4 hr treatment with 1 μM QC-01–175, the only significant changes observed comprise the validated immune-modulatory drug (IMiD) targets ZFP91, ZNF653 and ZNF827, while no QC-01–175 specific off-targets were observed. The negative control QC-03–075 (1 μM) revealed no effect on these proteins, confirming the ablation of CRBN-binding activity

Potency assay (off target): QC-01–175 was tested in an in vitro MAO assay showing high selectivity with IC50 > 8500 nM compared to warhead T807 which has IC50 140 nM.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

QC-01-175 is not a potent tau degrader, but it is well validated, so this compound is one of the good options to evaluate the biological effect of eliminating mutant tau from neurons.

(last updated: 19 Aug 2023 )

SERP Ratings

In Cell Rating

SERP Comments:

QC-01-175 can be considered as a pathfinder probe for tau degradation. For example this compound can be used for assay validation purposes. However, its lack of selectivity precludes use for cell biology studies. The published selectivity data show potent degradation of various Zn finger transcription factors as would be expected from its chemical structure. This probe is polypharmacological by nature.

(last updated: 27 Aug 2023 )

SERP Ratings

In Cell Rating

SERP Comments:

Considering that MS-based proteomic profiling of QC-01-175 in A152T neurons was conducted at a concentration of 1 uM, it is important to note that the selectivity of this probe at 10 uM remains unknown. Therefore, I suggest employing QC-01-175 in cell-based assays at both 1 uM and 10 uM concentrations. When interpreting the data obtained at 10 uM, one should take into account the results obtained at 1 uM as a reference point. Since cellular efficacy was confirmed at 1 uM, using QC-01-175 at this concentration should produce anti-tau efficacy in any cell-based model. Additionally, observing a dose-dependent response, with a stronger efficacy at 10 uM, will provide some validation of on-target engagement and enable more robust data interpretation.

(last updated: 8 Sept 2023 )