d9A-2

d9A-2 : Degrader (PROTAC) of SLC9A1

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(0 ratings)

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Probe d9A-2 is in the process of SERP review.

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Information

SLC9A1

Degrader (PROTAC)

250-750 nM
Reviewer recommended concentration: 250-500 nM

DOI - 10.1016/j.chembiol.2020.04.003

Probe Availability:

Sigma-Aldrich

In Vitro Validations

Uniprot ID: P19634

Target Class: Ion Channel

Target SubClass: Cation Proton Antiporter

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

Structure-activity relationship: no

Target aliases:

Sodium/hydrogen exchanger 1, NHE1, APNH1, SLC9A1, ...

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay (off target): Selectivity for the degradation of SLC9A1 over other SLC9 family members. HAP1 cells, overexpressing tagged proteins, corresponding to 11 members of the SLC9 family (A1, A2, A3, A4, A5, A6, A7, A8, A9, B1, and B2) were analysed after 16 h post-treatment with d9A-2 at 250 or 750 nM.

Probe Selectivity in Vitro:

SLC9A1 demonstrated the most efficient degradation. d9A-2 prompted degradation of the closely related SLC9A2 and SLC9A4, and also prompted degradation of the more distant SLC9A7 and SLC9B1. Comparatively, the abundance of the other assayed SLCs was less significantly affected at these experimental conditions. SLC9A1, SLC9A2, and SLC9A4 (but not SLC9A6) degraded at similar time kinetics.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

CRBN recruiting PROTAC d9A-2 is currently (December 2023) the best available degrader of for studying the biology of SLC9 transporters, although it has certain drawbacks. Based on the data in the original publication, d9A-2 exhibits the most potent degradation of SLC9A1 as its main target. d9A-2 is further capable of potent degradation of SLC9A2 and SLC9A4 and shows also degradation of SLC9A5, SLC9A6, SLC9A7, SLC9A8 and SLC9B1. PROTACd9A-2 has been profiled against 11 members of SLC transporters (SLC9A/B) therefore the knowledge about its selectivity profile is insufficient. The corresponding negative control compound is missing (e.g. d9A-2 analogue with methylated imid). The mechanism of degradation was probed using CRBN knockout cell line, competition experiment with pomalidomide and via cotreatment with neddylation and proteasomal inhibitors. Since cytotoxicity has been evaluated only at a 72 hour time point (showing strong cytotox effect in some cell lines), it would be desirable for the potential users to determine the cytotoxic affects also at shorter time points, according to the indented use. With my comments above I don't want to diminish the important scientific contribution of the original publication witch showed for the first time that SLCs are amenable for PROTAC mediated degradation.

(last updated: 28 Dec 2023 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

There seems to be a variability of the optimal dosing depending on pH and cell line used.

(last updated: 31 Oct 2024 )