Abstract
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.
Highlights
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the fusion gene Bcr-Abl, which is generated by a chromosomal translocation of the Abl gene on chromosome 9 to the Bcr gene on chromosome 22 to give a constitutively active protein tyrosine kinase, BCR-ABL1–5
SNIPERs and PROTACs are chimeric molecules composed of two different ligands connected by a linker; one ligand is for the target protein and the other is for E3 ubiquitin ligases
We found that drug removal after short-term treatment with inhibitors resulted in the rapid recovery of CML cell growth, whereas use of a degrader showed more sustained CML growth inhibition under the same condition
Summary
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the fusion gene Bcr-Abl, which is generated by a chromosomal translocation of the Abl gene on chromosome 9 to the Bcr gene on chromosome 22 to give a constitutively active protein tyrosine kinase, BCR-ABL1–5. Several BCR-ABL tyrosine kinase inhibitors (TKIs) have been discovered and approved for CML treatment[6,7,8,9]. These TKIs are capable of saving most CML patients; a significant number of patients develop drug resistance, which is commonly caused by point mutations in the tyrosine kinase domain of BCR-ABL. SNIPERs and PROTACs are chimeric molecules composed of two different ligands connected by a linker; one ligand is for the target protein and the other is for E3 ubiquitin ligases. The degraders inhibit BCR-ABL tyrosine kinase activity, which complicates the value and suitability of BCR-ABL degradation in CML cell growth inhibition by degraders. We discuss a possible mechanism of the sustained inhibition of CML cell growth by BCR-ABL degraders
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