title: Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis.
abstract: Chronic myelogenous leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl and treated with the tyrosine kinase inhibitor (TKI) imatinib. However, emerging TKI resistance prevents complete cure. Therefore, alternative strategies targeting regulatory modules of Bcr-Abl in addition to the kinase active site are strongly desirable. Here, we show that an intramolecular interaction between the SH2 and kinase domains in Bcr-Abl is both necessary and sufficient for high catalytic activity of the enzyme. Disruption of this interface led to inhibition of downstream events critical for CML signaling and, importantly, completely abolished leukemia formation in mice. Furthermore, disruption of the SH2-kinase interface increased sensitivity of imatinib-resistant Bcr-Abl mutants to TKI inhibition. An engineered Abl SH2-binding fibronectin type III monobody inhibited Bcr-Abl kinase activity both in vitro and in primary CML cells, where it induced apoptosis. This work validates the SH2-kinase interface as an allosteric target for therapeutic intervention.
authors: Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors: Florian
authors: F
authors: Grebien
authors: Oliver
authors: O
authors: Hantschel
authors: John
authors: J
authors: Wojcik
authors: Ines
authors: I
authors: Kaupe
authors: Boris
authors: B
authors: Kovacic
authors: Arkadiusz M
authors: AM
authors: Wyrzucki
authors: Gerald D
authors: GD
authors: Gish
authors: Sabine
authors: S
authors: Cerny-Reiterer
authors: Akiko
authors: A
authors: Koide
authors: Hartmut
authors: H
authors: Beug
authors: Tony
authors: T
authors: Pawson
authors: Peter
authors: P
authors: Valent
authors: Shohei
authors: S
authors: Koide
authors: Giulio
authors: G
authors: Superti-Furga
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001549:Benzamides; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007532:Isoleucine / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D007532:Isoleucine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl