PIM-447

Protein target name:

PIM1, PIM2, PIM3

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 500 nM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

CAMK

HUGO ID:

HGNC:8986 HGNC:8987 HGNC:19310

Entrez gene ID:

5292 11040 415116

UNIPROT ID:

P11309 Q9P1W9 Q86V86

Target alias:

PIM, PIM-3

Probe Details

Chemical Probes Portal ID:

CPP2238

Probe alias:

LGH447, cpd 8, 5HZ

PubChem CID:

44814409

ChEMBL ID:

CHEMBL3651966

SMILES string:

O=C(NC1=C(C=CN=C1)[C@H]2C[C@H](C[C@H](C2)C)N)C3=NC(C4=C(C=CC=C4F)F)=C(C=C3)F

InChi Key:

VRQXRVAKPDCRCI-ZNMIVQPWSA-N

Control compound:

cpd 1

Orthogonal probe:

SGI-1776, AZD-1208

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.006 nM PIM10.018 nM PIM20.009 nM PIM3

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

Off target activity

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 nonmutant kinases including PIMs 1, 2, and 3; S(35) = 0.013 at 1 μM, 383 nonmutant kinases not including PIMs 1, 2, and 3].

In cell validation

On target activity in cells

Potency in cells:

EC50

170 nM

Potency assay (cells):

Antiproliferation activity assay

Off target activity in cells

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.

In vivo validation

Organism:

Mouse, Rat, Dog

Dose:

30 or 100 mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

3.3 (M), 2.8 (R), 6.7 (D) h

Systemic clearance:

20 (M), 28 (R), 8 (D) mL/min/Kg

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.5b01275

Reference (PMID):

26505898

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB 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.

Apr 10 2021 - 1:32pm

PIM-447

Probe Availability

Probe Information

Target Details

PIM, PIM-3

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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PIM-447

Probe Availability

Probe Information

Target Details

PIM, PIM-3

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?