Structural and Biochemical Basis for Intracellular Kinase Inhibition by Src-specific Peptidic Macrocycles.
Protein kinases are attractive therapeutic targets because their dysregulation underlies many diseases, including cancer. The high conservation of the kinase domain and the evolution of drug resistance, however, pose major challenges to the development of specific kinase inhibitors. We recently discovered selective Src kinase inhibitors from a DNA-templated macrocycle library. Here, we reveal the structural basis for how these inhibitors retain activity against a disease-relevant, drug-resistant kinase mutant, while maintaining Src specificity. We find that these macrocycles display a degree of modularity: two of their three variable groups interact with sites on the kinase that confer selectivity, while the third group interacts with the universally conserved catalytic lysine and thereby retains the ability to inhibit the "gatekeeper" kinase mutant. We also show that these macrocycles inhibit migration of MDA-MB-231 breast tumor cells. Our findings establish intracellular kinase inhibition by peptidic macrocycles, and inform the development of potent and specific kinase inhibitors.
Dept. of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794-8661, USA.
Saadat
S
Aleem
Dept. of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, USA.
George
G
Georghiou
Dept. of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Ralph E
RE
Kleiner
Dept. of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, USA.
Kip
K
Guja
Dept. of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794-8661, USA.
Barbara P
BP
Craddock
Dept. of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, USA.
Agatha
A
Lyczek
Dept. of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Alix I
AI
Chan
Dept. of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, USA.
Miguel
M
Garcia-Diaz
Dept. of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794-8661, USA.
W Todd
WT
Miller
Dept. of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.|Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
David R
DR
Liu
Dept. of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, USA.
Markus A
MA
Seeliger
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047028:Macrocyclic Compounds; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; C040475:Src peptide; D019061:src-Family Kinases