PIM-447

Inhibitor of PIM1, PIM2, PIM3

Structure

Information

  • PIM1
  • PIM2
  • PIM3
  • Inhibitor
  • up to 500 nM

In Vitro Validations

Uniprot ID: P11309
Target Class: Kinase
Target SubClass: CAMK
Potency: Ki
Potency Value: 0.006 nM
Potency Assay: Kinase-Glo assay, with [ATP] at or below ATP Km for each isoform
PDB ID for probe-target interaction (3D structure): 5DWR
Structure-activity relationship: yes
Target aliases:
Serine/threonine-protein kinase pim-1, PIM1, PIM1_ ...

DOI Reference: 10.1021/acs.jmedchem.5b01275

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:
Kinase selectivity was first determined in biochemical assays for a panel of 68 protein kinases and 9 lipid kinases. Only PIM2 was significantly inhibited with an IC50 of <0.003 μM, the lowest sensitivity range for the assay. Also, GSK3β, PKN1, and PKCτ were inhibited but at a significantly lower potency with IC50 between 1 and 5 μM. Additional kinase profiling against 442 kinases using the KINOMEscan at 1 uM, indicated high kinase selectivity [S(35) = 0.021 at 1 μM, 386 non-mutant kinases including PIMs 1, 2, and 3; S(35) = 0.013 at 1 μM, 383 non-mutant kinases not including PIMs 1, 2, and 3].
Probe Selectivity in Cell:
Cellular activity across an expanded panel of 26 AML cell lines was assessed with antiproliferative activity spanned a range from low nM to insensitivity at 10 μM, with approximately 1/3 sensitive at ≤500 nM, 1/3 sensitive between 500 nM and 3 μM, and 1/3 sensitive at <3 μM.
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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

PIM-447 is a pan-PIM 1, 2 and 3 kinase inhibitor that demonstrates potent biochemical activity and good selectivity in a 442 kinase panel. There is a large drop off to cellular activity in both antiproliferative and biomarker assays and the contribution of each isoform to the response in the cellular environment is unknown. The cellular biomarker used, pS6RP, is indirect which should be considered when interpreting this data. PIM-447 shows a strong effect in a mouse xenograft study, with a pharmacodynamic response consistent with the in vitro data. Apart from the kinase selectivity and hERG activity, no broad pharmacological profiling data has been provided to further validate use of PIM-447 in vivo.

(last updated: 10 Apr 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 10 Apr 2021 )