PIM447   Click here for help

GtoPdb Ligand ID: 9790

Synonyms: compound 8 [PMID: 26505898] | LGH-447 | LGH447 | PIM-447
PDB Ligand
Compound class: Synthetic organic
Comment: PIM447 is a potent and selective pan PIM kinase inhibitor [1], that is being investigated for clinical efficacy against hematological malignancies.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 5
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 80.9
Molecular weight 440.18
XLogP 4.22
No. Lipinski's rules broken 0
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Canonical SMILES CC1CC(N)CC(C1)c1ccncc1NC(=O)c1ccc(c(n1)c1c(F)cccc1F)F
Isomeric SMILES C[C@@H]1C[C@H](N)C[C@@H](C1)c1ccncc1NC(=O)c1ccc(c(n1)c1c(F)cccc1F)F
InChI InChI=1S/C24H23F3N4O/c1-13-9-14(11-15(28)10-13)16-7-8-29-12-21(16)31-24(32)20-6-5-19(27)23(30-20)22-17(25)3-2-4-18(22)26/h2-8,12-15H,9-11,28H2,1H3,(H,31,32)/t13-,14+,15-/m0/s1
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Summary of Clinical Use Click here for help
A Phase 1 clinical trial evaluating PIM447 in double and triple combinations with ruxolitinib (a JAK1/2 inhibitor) and/or ribociclib (a CDK4/6 inhibitor) in patients with myelofibrosis is underway (see NCT02370706). First-in-human results from patients with relapsed/ refractory multiple myeloma provided proof of principle for PIM kinase inhibition as a novel therapeutic approach in multiple myeloma (Raab et al., May 2019) [2].
Mechanism Of Action and Pharmacodynamic Effects Click here for help
PIM kinases function in the survival, proliferation, and differentiation of hematopoietic cells in response to growth factors and cytokines. All three PIM genes have oncogenic potential, with evidence showing that aberrant PIM expression is implicated in the progression of hematopoietic and solid tumours. Pan-PIM kinase inhibitors are being investigated for antineoplastic activity, as they will combat the functional redundancy of the PIM isoforms.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02370706 Study of the Safety of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 in Patients With Myelofibrosis Phase 1 Interventional Novartis