Development of protein degradation inducers of oncogenic BCR‐ABL protein by conjugation of ABL kinase inhibitors and IAP ligands

Abstract

Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR‐ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long‐term treatment. An alternative approach to treat CML is to downregulate the BCR‐ABL protein. We have devised a protein knockdown system by hybrid molecules named Specific and Non‐genetic inhibitor of apoptosis protein [IAP]‐dependent Protein Erasers (SNIPER), which is designed to induce IAP‐mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR‐ABL protein have been developed recently. In this study, we tested various combinations of ABL inhibitors and IAP ligands, and the linker was optimized for protein knockdown activity of SNIPER(ABL). The resulting SNIPER(ABL)‐39, in which dasatinib is conjugated to an IAP ligand LCL161 derivative by polyethylene glycol (PEG) × 3 linker, shows a potent activity to degrade the BCR‐ABL protein. Mechanistic analysis suggested that both cellular inhibitor of apoptosis protein 1 (cIAP1) and X‐linked inhibitor of apoptosis protein (XIAP) play a role in the degradation of BCR‐ABL protein. Consistent with the degradation of BCR‐ABL protein, the SNIPER(ABL)‐39 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and Crk like proto‐oncogene (CrkL), and suppressed the growth of BCR‐ABL‐positive CML cells. These results suggest that SNIPER(ABL)‐39 could be a candidate for a degradation‐based novel anti‐cancer drug against BCR‐ABL‐positive CML.

PHOTACs enable optical control of protein degradation

“…The modularity of our approach should enable the straightforward development of PHOTACs that target many other classes of proteins. For instance, existing PROTACs that target CDK4/6 (30), CDK9 (16), BTK (19,20), ABL (17,39), ALK (anaplastic lymphoma kinase) (40), MET (18), MDM2 (murine double minute 2) (41), and Tau (42) could be adapted to become light activatable. Our PHOTACs for BRD2,3,4 may enable new in sights into epigenetic pathways and potentially serve as precision tools in medicine.…”

A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL

“…Pioneering studies by the Crews lab have shown that BCR-ABL PROTACs, consisting of CRBN or VHL recruiters linked to BCR-ABL ATP binding pocket-targeting kinase inhibitors such as dasatinib and bosutinib or allosteric inhibitors such as GNF-2, showed preferential degradation of c-ABL over modest degradation of BCR-ABL (Burslem et al, 2019;Lai et al, 2016). Notably, this work has spurred development of various degradation strategies targeting BCR-ABL (Demizu et al, 2016;Shibata et al, 2017Shibata et al, , 2019Shimokawa et al, 2017;Zhao et al, 2019). In this study, we aimed to determine whether our recently discovered covalent RNF114 recruiter nimbolide could be used to kinase-targeting PROTACs, and if so, whether differential selectivity in degrading BCR-ABL, compared to similar BCR-ABL PROTACs employing VHL or CRBN could be attained.…”

Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein

“…As a proof-of-concept study, we designed and synthesized a series of hybrid molecules consisting of MeBS and all-trans retinoic acid, and found that they induced the proteasomal degradation of cellular retinoic acid binding protein-II. 18,19,21,29) Then, we developed various hybrid molecules by connecting tamoxifen, androgen receptor (AR) antagonists, and KHS-108 to MeBS, which induce the degradation of estrogen receptor (ER), 20,22) AR, 34) and transforming acidic coiled-coil containing protein 3, 23,27) respectively. In addition to these targets, HaloTag-fused proteins 24,26) and huntingtin 32) were successfully degraded by bestatin-based SNIPERs.…”