Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase

Chronic myelogenous leukemia (CML) is characterized by the oncogenic fusion protein, Bcr-Abl protein kinase, against which clinically useful inhibitors have been developed. An alternative approach to treat CML is to degrade the Bcr-Abl protein. Recently, potent degraders against Bcr-Abl have been developed by conjugating dasatinib to ligands for E3 ubiquitin ligases. Since the degraders contain the dasatinib moiety, they also inhibit Bcr-Abl kinase activity, which complicates our understanding of the impact of Bcr-Abl degradation by degraders in CML growth inhibition. To address this issue, we chose DAS-IAP, as a potent Bcr-Abl degrader, and developed a structurally related inactive degrader, DAS-meIAP, which inhibits kinase activity but does not degrade the Bcr-Abl protein. DAS-IAP showed slightly weaker activity than DAS-meIAP in inhibiting cell growth when CML cells were treated for 48 h. However, DAS-IAP showed sustained growth inhibition even when the drug was removed after short-term treatment, whereas CML cell growth rapidly resumed following removal of DAS-meIAP and dasatinib. Consistently, suppression of Bcr-Abl levels and downstream kinase signaling were maintained after DAS-IAP removal, whereas kinase signaling rapidly recovered following removal of DAS-meIAP and dasatinib. These results indicate that Bcr-Abl degrader shows more sustained inhibition of CML cell growth than ABL kinase inhibitor.