3EN4

Targeted polypharmacology: crystal structure of the c-Src kinase domain in complex with PP121, a multitargeted kinase inhibitor

Summary for 3EN4

• Entry DOI: 10.2210/pdb3en4/pdb
• Related: 3EN5 3EN6 3EN7
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, 1-cyclopentyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• Functional Keywords: src, tyrosine, kinase, polypharmacology, inhibitor, multitarget, phosphoinositide, transferase, signaling, pyrazolopyrimidine, kinase-inhibitor complex, atp-binding, lipoprotein, myristate, nucleotide-binding, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, tyrosine-protein kinase
• Biological source: Gallus gallus (bantam,chickens)
• Cellular location: Cell membrane : P00523
• Total number of polymer chains: 2
• Total formula weight: 66092.02

Authors

Blair, J.A.,Apsel, B.,Knight, Z.A.,Shokat, K.M. (deposition date: 2008-09-25, release date: 2008-10-14, Last modification date: 2023-09-06)

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

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: 18849971
DOI: 10.1038/nchembio.117

Experimental method

X-RAY DIFFRACTION (2.55 Å)