Targets for molecular therapy.

Each target is numbered and marked with a “target” sign. 1. The SH1 or tyrosine kinase domain of Bcr-Abl: its activity can be inhibited by signal transduction inhibitors, such as imatinib mesylate or adaphostin. 2. The dimerization (coiled-coil) domain of Bcr-Abl: deletion/mutation or blocking of this domain with peptides that prevent oligomerization renders Bcr-Abl nontransforming. 3. Heat-shock protein 90 (Hsp90): Hsp90 functions as chaperone that maintains the stability of the Bcr-Abl protein; antagonists of Hsp90, such as geldanamycin, destabilize Bcr-Abl and promote its proteasomal degradation. 4. BCR-ABL mRNA: synthesis of the Bcr-Abl oncoprotein may be suppressed by inhibiting BCR-ABL mRNA by either antisense oligonucleotides, siRNA molecules, ribozymes or DNAzymes. 5. The SH3 domains of the adapter proteins Grb2 or CrkL: synthetic peptides that bind to these domains “uncouple” Bcr-Abl from downstream signaling pathways. 6. Farnesyl transferase: inhibitors of farnesyl transferase suppress Ras signaling by preventing the attachment of a farnesyl group to Ras; farnesyl groups are essential for the normal functioning of Ras since they tether these G-proteins to the plasma membrane. 7. Mek (MAPK or ERK Kinase): Bcr-Abl constitutively activates the Ras-Raf-Mek-Erk pathway; Mek inhibitors may be useful for inhibiting this mitogenic cascade 8. PI-3 kinase: PI-3 kinase associates with Bcr-Abl and undergoes activation as a result of tyrosine phosphorylation; PI-3 kinase cell signaling may be inhibited with compounds such as wortmannin or LY294002, resulting in apoptosis by activation of Bad (proapoptotic) via Akt and its dissociation from Bcl-X_L (antiapoptotic). 9. mTOR: this PI-3 kinase effector and two of its substrates, ribosomal protein S6 and 4E-BP1, are constitutively phosphorylated in a Bcr-Abl-dependent manner; the pathway can be inhibited by rapamycin.