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Rentosertib

Rentosertib : Inhibitor of TNIK

Structure

Information

  • TNIK
  • Inhibitor
  • up to 1 uM

In Vitro Validations

Uniprot ID: Q9UKE5
Target Class: Kinase
Target SubClass: STE
Potency: IC50
Potency Value: 31 nM
Potency Assay: Enzymatic assay
PDB ID for probe-target interaction (3D structure): 8ZML
Target aliases:
TRAF2 and NCK-interacting protein kinase, KIAA0551 ...

DOI Reference: 10.1021/acs.jmedchem.4c01580

Uniprot ID: Q9UKE5
Target Class: Kinase
Target SubClass: STE
Potency: Kd
Potency Value: 4.3 nM
Potency Assay: SPR assay
PDB ID for probe-target interaction (3D structure): --
Target aliases:
TRAF2 and NCK-interacting protein kinase, KIAA0551 ...

DOI Reference: 10.1021/acs.jmedchem.4c01580

Uniprot ID: Q9UKE5
Target Class: Kinase
Target SubClass: STE
Potency: IC50
Potency Value: 14.7 nM
Potency Assay: FRET assay @ 64 uM ATP
PDB ID for probe-target interaction (3D structure): --
Target aliases:
TRAF2 and NCK-interacting protein kinase, KIAA0551 ...

DOI Reference: 10.1021/acs.jmedchem.4c01580

Uniprot ID: Q9UKE5
Target Class: Kinase
Target SubClass: STE
Potency: IC50
Potency Value: 7.8 nM
Potency Assay: Radiometric assay
PDB ID for probe-target interaction (3D structure): --
Target aliases:
TRAF2 and NCK-interacting protein kinase, KIAA0551 ...

DOI Reference: 10.1021/acs.jmedchem.4c01580

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): Rentosertib was profiled in an off-target panel of 78 proteins, including GPCRs, nuclear receptors, ion channels, transporters, and various enzymes. No activity was found across these targets except for low to moderate potency against two kinases, LCK and VEGFR2, and 7-transmembrane receptor CHRM1.
Potency assay (off target): Rentosertib was screened at the dose of 10 μM against a panel of 430 enzymes, which consists of both protein and lipid kinases. The results of this screening were expressed as remaining kinase activity after compound treatment normalized to the DMSO control. In total, 43 human kinases with remaining activity under 20% after incubation with Rentosertib were observed. Next, Rentosertib was assayed against each of these kinases in a dose–response manner at the ATP concentration equaled to a kinase’s Km value. TNIK was inhibited by Rentosertib with the highest potency (IC50 of 31 nM). Interestingly, the dose-dependent study did not confirm the results of single-dose screening for Aurora-B and ErbB4. Indeed, Rentosertib demonstrated IC50 > 10 μM against these enzymes. In addition to TNIK, five kinases were inhibited with IC50 < 100 nM, three of which were mutants (PDGFRα, Kit, and EGFR), and two were wild type (YES and ALK4). Notably, nonmutant Kit and PDGFRα were out of the 43 hit kinases list, whereas EGFR was inhibited in a micromolar range.
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Compound 4 (rentosertib) is a potent TNIK kinase inhibitor with an IC50 of 7.8nM in a radiometric assay and a Kd of 4.3nM as measured by SPR. However, there are no published direct target engagement data. Nevertheless, it exhibits antifibrotic and anti-inflammatory activity in cellular and in vivo models, which is consistent with the biology of TNIK. Rentosertib also reduced TGF-β-mediated α-SMA expression in lung fibroblast cells (MRC-5) with an IC50 of 27nM, as well as in fibroblasts from donors with IPF (IC50s of 50-63nM), without substantially causing cytotoxicity. The paper refers to screening data in which this inhibitor was tested against a panel of 430 kinases. However, I could not access these data in 10.1021/acs.jmedchem.4c01580 or in the referenced paper (Ren et al., Nat. Biotechnol., 2024). According to the paper's description, Compound 4 inhibited five kinases with IC50 values below 100nM. However, three of the identified off-targets were mutants (PDGFRα, Kit, and EGFR), and the wild-type kinases were not inhibited. The two additional wild-type kinases were YES and ALK4. This is certainly a potent TNIK inhibitor and probably the "best in class" chemical probe for this target. There is no negative control compound.

(last updated: 19 Dec 2025 )