Targeting the Myristoyl Binding Pocket in BCR/ABL: A Rational Approach for the Design of Molecular Therapy Against Philadelphia Chromosome-Positive Leukemia

• Antragsteller: Privatdozent Dr. Martin Ruthardt
• Mitantragsteller: Professor Dr. Amiram Goldblum; Professor Dr. Jamal Mahajna; Professor Dr. Yousef Najajreh, Ph.D.
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2006 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 30388368

The cytogenetic correlate of the t(9;22) is the Philadelphia chromosome. 95% of patients suffering from chronic myeloid leukemia (CML) and 25-30% of patient with acute lymphatic leukemia (ALL) are Philadelphia chromosome-positive (Ph+). The t(9;22) leads to the formation of the chimeric bcr/abl fusion gene which encodes for the BCR/ABL fusion protein. In contrast to its physiological counterpart c-ABL, whose kinase activity is finely regulated by growth factors and other stimuli, BCR/ABL is constitutively activated. Thus it aberrantly activates down-stream signaling pathways such as RAS, PI3 Kinase/AKT as well as JAK/STAT inducing the leukemic phenotype. In the BCR/ABL fusion protein, the N-terminus part of ABL is replaced with the N-terminus part of BCR. Recently, the N-terminus end (Cap region) of ABL was implicated in regulating the kinase function of ABL. The N-terminus of ABL is myristoylated, and the myristate residue binds to a hydrophobic pocket in the kinase domain (Myristoyl binding pocket, MBP), a process called capping . The capping turns c-ABL into an auto-inhibited conformation. The N-terminal auto-inhibitory Cap region is absent in the BCR/ABL allowing the fusion protein to escape the autoinhibition. This lack of auto-inhibition mainly contributes to the constitutive activation of BCR/ABL. Based on the crystal structure of c-ABL in complex with myristic acid and with myristoyl from the N-terminal domain we propose to inhibit the constitutive activation of BCR/ABL by myristoyl mimics which compete for the MBP. These mimics will be designed for selectivity versus Src family kinases which could have a similar mechanism of auto-inhibition. Such competitors will be designed by innovative computer methods, synthesized and screened for their efficacy in several leukemia models.

• DFG-Verfahren: Sachbeihilfen
• Internationaler Bezug: Israel, Palästina