4XHK

PIM1 kinase in complex with Compound 1s

Summary for 4XHK

• Entry DOI: 10.2210/pdb4xhk/pdb
• Related: 4X7Q
• Descriptor: Serine/threonine-protein kinase pim-1, 2-(2,6-difluorophenyl)-N-{4-[(3S)-pyrrolidin-3-yloxy]pyridin-3-yl}-1,3-thiazole-4-carboxamide (3 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• Total number of polymer chains: 1
• Total formula weight: 36369.31

Authors

Marcotte, D.J.,Silvian, L.F. (deposition date: 2015-01-05, release date: 2015-02-11, Last modification date: 2024-10-16)

Primary citation

Ishchenko, A.,Zhang, L.,Le Brazidec, J.Y.,Fan, J.,Chong, J.H.,Hingway, A.,Raditsis, A.,Singh, L.,Elenbaas, B.,Hong, V.S.,Marcotte, D.,Silvian, L.,Enyedy, I.,Chao, J.
Structure-based design of low-nanomolar PIM kinase inhibitors.
Bioorg.Med.Chem.Lett., 25:474-480, 2015

PubMed Abstract: PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein-ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile.

PubMed: 25575657
DOI: 10.1016/j.bmcl.2014.12.041

Experimental method

X-RAY DIFFRACTION (1.9 Å)