2C3I

CRYSTAL STRUCTURE OF HUMAN PIM1 IN COMPLEX WITH IMIDAZOPYRIDAZIN I

Summary for 2C3I

• Entry DOI: 10.2210/pdb2c3i/pdb
• Related: 1XQZ 1XR1 1XWS 1YHS 1YI3 1YI4 1YWV 1YXS 1YXT 1YXU 1YXV 1YXX 2BIK 2BIL 2BZH 2BZI 2BZJ 2BZK
• Descriptor: PIMTIDE, PROTO-ONCOGENE SERINE THREONINE PROTEIN KINASE PIM1, 1-(3-{6-[(CYCLOPROPYLMETHYL)AMINO]IMIDAZO[1,2-B]PYRIDAZIN-3-YL}PHENYL)ETHANONE, ... (4 entities in total)
• Functional Keywords: transferase-peptide complex, complex transferase-peptide, pim1, kinase, cancer, leukemia, atp-binding, nuclear protein, nucleotide-binding, phosphorylation, proto- oncogene, serine/threonine-protein kinase, transferase, transferase/peptide
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• Total number of polymer chains: 2
• Total formula weight: 36937.13

Authors

Philippakopoulos, P.,Knapp, S.,Debreczeni, J.,Bullock, A.,von Delft, F.,Sundstrom, M.,Arrowsmith, C.,Edwards, A.,Guo, K.,Weigelt, J. (deposition date: 2005-10-07, release date: 2005-11-01, Last modification date: 2023-12-13)

Primary citation

Pogacic, V.,Bullock, A.N.,Fedorov, O.,Filippakopoulos, P.,Gasser, C.,Biondi, A.,Meyer-Monard, S.,Knapp, S.,Schwaller, J.
Structural Analysis Identifies Imidazo[1,2- B]Pyridazines as Pim Kinase Inhibitors with in Vitro Antileukemic Activity.
Cancer Res., 67:6916-, 2007

PubMed Abstract: Much attention has recently been focused on PIM kinases as potential targets for the treatment of hematopoietic malignancies and some solid cancers. Using protein stability shift assays, we identified a family of imidazo[1,2-b]pyridazines to specifically interact with and inhibit PIM kinases with low nanomolar potency. The high-resolution crystal structure of a PIM1 inhibitor complex revealed that imidazo[1,2-b]pyridazines surprisingly interact with the NH(2)-terminal lobe helix alphaC rather than with the kinase hinge region. Thus, the identified inhibitors are ATP competitive but not ATP mimetic compounds, explaining their enhanced selectivity with respect to conventional type I kinase inhibitors. One of the identified imidazo[1,2-b]pyridazines (K00135) was further tested in several hematopoietic cellular systems. First, K00135 dose-dependently impaired survival of murine Ba/F3 cells that have been rendered cytokine independent by overexpression of human PIMs. Second, K00135 impaired survival and clonogenic growth of a panel of human acute leukemia cells. Third, exposure of K00135 significantly suppressed in vitro growth of leukemic blasts from five acute myelogenous leukemia patients but not of normal umbilical cord blood mononuclear cells. In vitro kinase assays and immunoblotting using lysates from human MV4;11 leukemic cells showed inhibition of phosphorylation of known PIM downstream targets, such as BAD and eukaryotic translation initiation factor 4E-binding protein 1, by K00135. Taken together, we report a family of small molecules that selectively interact and block PIM kinases and could serve as a lead to develop new targeted antileukemic therapeutics.

PubMed: 17638903
DOI: 10.1158/0008-5472.CAN-07-0320

Experimental method

X-RAY DIFFRACTION (1.9 Å)