NVS-PAK1-1

Allosteric inhibitor of PAK1

Structure

Information

  • PAK1
  • Allosteric inhibitor
  • 400 nM - 2 uM

In Vitro Validations

Uniprot ID: Q13153
Target Class: Kinase
Target SubClass: STE
Potency: IC50
Potency Value: 5 nM
Potency Assay: Caliper IC50 assay. IC50 values were derived from % inhibition values at different compound concentrations by non-linear regression analysis.
PDB ID for probe-target interaction (3D structure): 4ZLO 4ZJJ 4ZLI
Structure-activity relationship: Biochemical potency SAR described in ACS Med. Chem. Lett. 2015, 6 (7), pp 776–781
Target aliases:
Serine/threonine-protein kinase PAK 1, PAK1, PAK1_ ...

DOI Reference: 10.1021/acsmedchemlett.5b00102

Uniprot ID: Q13153
Target Class: Kinase
Target SubClass: STE
Potency: Kd
Potency Value: 7 nM
Potency Assay: DiscoverX
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Serine/threonine-protein kinase PAK 1, PAK1, PAK1_ ...

DOI Reference: 10.1021/acsmedchemlett.5b00102

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : KD PAK2=400 nM
Potency assay (off target): Selectivity for PAK1 > PAK2 = 57-fold. It demonstrated a selectivity score (S10-score) of 0.003 when tested at 10 μM against 442 kinases in the KinomeScan competition binding assay (DiscoveRx).
Probe Selectivity in Vitro:
No significant inhibition of CYP450s (13.2 μM for 3A4 the midazolam site, >20 μM for 2D6 and 16.7 μM for 2C9)
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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

NVS-PAK1-1 is a potent PAK1 inhibitor with exclusive selectivity for this kinase. Structural studies revealed an allosteric binding mode. This inhibitor is highly potent in cellular assays but showed poor stability in vivo. Thus, in vivo use is not recommended without further improvement of pharmacological properties. It is an excellent inhibitor for functional studies on PAK1 kinase.

(last updated: 18 Mar 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

NVS-PAK1-1 is a potent, allosteric PAK1 inhibitor. It is about 60-fold selective over PAK2. It is highly selective over other kinases in the kinome. It has a submicromolar IC50 in a PAK1 autophosphorylation assay. These features make it a useful tool to assess the impact of PAK1 inhibition in a cellular context. More data would need to be collected, but poor microsomal stability (rat) suggests the compound may not be suitable for use in model organisms (in vivo applications).

(last updated: 18 Mar 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

Rudolph et al., J Med Chem 2016 demonstrate that class I PAK inhibitors from two structurally distinct classes reveal persistent cardiovascular toxicity and correlate minimum toxic concentrations with PAK1/2-mediated cellular potencies. Broad screening of selected PAK inhibitors reveals that PAK1, 2, and 3 as the only overlapping targets. This data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition. This manuscript cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery.

(last updated: 19 Mar 2017 )

Portal Comments

In a 2023 study, Hu et al. evaluated NVS-PAK1-1 in live-cell assays for Phospholipidosis induction, cautioning about adverse effects at concentrations equal or exceeding 1 uM. (DOI: 10.1016/j.chembiol.2023.09.003)

(last updated: 7 Nov 2023)