3ENE
Complex of PI3K gamma with an inhibitor
Summary for 3ENE
| Entry DOI | 10.2210/pdb3ene/pdb |
| Descriptor | Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 1-methyl-3-naphthalen-2-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total) |
| Functional Keywords | lipid kinase, phosphoinositide, inhibitor, 3-kinase, signaling, pyrazolopyrimidine, pik-208, s2, kinase, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 110071.37 |
| Authors | Apsel, B.,Blair, J.A.,Gonzalez, B.Z.,Nazif, T.M.,Feldman, M.E.,Williams, R.L.,Shokat, K.M.,Knight, Z.A. (deposition date: 2008-09-25, release date: 2008-10-14, Last modification date: 2023-11-01) |
| Primary citation | Apsel, B.,Blair, J.A.,Gonzalez, B.,Nazif, T.M.,Feldman, M.E.,Aizenstein, B.,Hoffman, R.,Williams, R.L.,Shokat, K.M.,Knight, Z.A. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases Nat.Chem.Biol., 4:691-699, 2008 Cited by PubMed Abstract: The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes. PubMed: 18849971DOI: 10.1038/nchembio.117 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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