Scientists at UCSF have developed a novel class of BCR-ABL inhibitors that engages two binding sites in BCR-ABL simultaneously. This two-site binding (bitopic) mechanism of action is unprecedented against BCR-ABL, one of the most well-validated targets in oncology.
Classically, inhibitors bind to their targets through singular, well-formed pockets. In the case of chronic myeloid leukemia (CML), a disease characterized by its nearly absolute association with BCR-ABL dependency, the approved drugs directed against BCR-ABL only target a single binding site and cause a mixture of off-target toxicity issues. In addition to the off-target effects, commonly observed resistance mutations preclude the recognition of any single ‘optimal’ therapeutic regiment for CML that is able to universally enable patients to live normal lifespans or achieve a cure.
This novel invention provides the following advantages:
UCSF researchers have synthesized two classes bitopic inhibitors of BCR-ABL that have been verified for their biochemical activity against ABL1 kinase domain and validated for their ability to specifically inhibit BCR-ABL signaling in cells. Further optimization can be done in both the ligand and linker components and additional biological validation will be needed prior to clinical trial.
To develop and commercialize this technology.
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