IR-2

IR-2 : Degrader (PROTAC) of BTK

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(0 ratings)

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Information

Degrader (PROTAC)

100 nM

In Vitro Validations

Uniprot ID: Q06187

Target Class: Kinase

Target SubClass: TK

Potency: IC50

Potency Value: 14 nM

Potency Assay: Inhibition of BTK

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

Target aliases:

Tyrosine-protein kinase BTK, AGMX1, BTK, BTK_HUMAN ...

DOI Reference: 10.1021/jacs.9b13907

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay (off target): Quantitative label-free proteomics

Probe Selectivity in Vitro:

BTK was efficiently degraded by all the PROTACs we tested. IR-2 also degraded the known ibrutinib off-targets CSK, LYN, and BLK, while several other off-targets, such as LCK and PLK1, were not significantly affected.

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SERP ratings and comments

SERP Ratings

In Cell Rating

(last updated: 23 Mar 2022 )

SERP Ratings

In Cell Rating

(last updated: 26 Mar 2022 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

This well characterised PROTAC, IR-2, demonstrated a DC50 in the low nanomolar range in two cell lines (Mino and CLL patient samples). However, off-target degradation has been seen by proteomics for CSK, BLK and LYN which are known off-targets for ibrutinib. In-cell target engagement was demonstrated through competition with ibrutinib and thalidomide-OH, and the proteasome dependent mechanism of action has been confirmed using proteasome inhibitor bortezomib. The PROTAC shows a Hook effect at >100 nM. We therefore recommend an in-cell concentration of 50 nM. The observed phenotypic response demonstrated in mouse primary B-cells are in line with ibrutinib treatment. Unfortunately, no cytotoxicity or solubility data have been provided. The degradation of mutant BTK C481S demonstrates a non-covalent MoA.

(last updated: 6 Feb 2026 )