Sequence-based design of kinase inhibitors applicable for therapeutics and target identification.
A platform for specifically modulating kinase-dependent signaling using peptides derived from the catalytic domain of the kinase is presented. This technology, termed KinAce, utilizes the canonical structure of protein kinases. The targeted regions (subdomain V and subdomains IX and X) are analyzed and their sequence, three-dimensional structure, and involvement in protein-protein interaction are highlighted. Short myristoylated peptides were derived from the target regions of the tyrosine kinases c-Kit and Lyn and the serine/threonine kinases 3-phosphoinositide-dependent kinase-1 (PDK1) and Akt/protein kinase B (PKB). For each kinase an active designer peptide is shown to selectively inhibit the signaling of the kinase from which it is derived, and to inhibit cancer cell proliferation in the micromolar range. This technology emerges as an applicable tool for deriving sequence-based selective inhibitors for a broad range of protein kinases as hits that may be further developed into drugs. Moreover, it enables identification of novel kinase targets for selected therapeutic indications as demonstrated in the KinScreen application.
Niv
Masha Y
MY
Keryx Biopharmaceuticals, 15 Yad-Haruzim St., Jerusalem 93420, Israel.
Rubin
Hila
H
Cohen
Jacob
J
Tsirulnikov
Lilia
L
Licht
Tamar
T
Peretzman-Shemer
Adi
A
Cna'an
Einat
E
Tartakovsky
Alexander
A
Stein
Ilan
I
Albeck
Shira
S
Weinstein
Irina
I
Goldenberg-Furmanov
Mirela
M
Tobi
Dror
D
Cohen
Einat
E
Laster
Morris
M
Ben-Sasson
Shmuel A
SA
Reuveni
Hadas
H
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000378:metabolism; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D002474:Cell-Free System; D003001:Cloning, Molecular; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003600:Cytosol / Q000378:metabolism; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009227:Myristic Acids / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D009227:Myristic Acids; D010455:Peptides; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005982:Glutathione Transferase; D019009:Proto-Oncogene Proteins c-kit; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494918:AKT1 protein, human; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt