The Activity of Novel BCR-ABL Small-Molecule Degraders Containing Pyrimidine Rings and Their Role in Overcoming Drug Resistance

Abstract

Inducing protein degradation by proteolysis-targeting chimeras (PROTACs) has gained tremendous momentum in the field for its promise in the discovery and development of new therapies. Based on our previously reported PROTAC BCR-ABL degraders, we designed and synthesized additional 4 PROTAC compounds with a novel linker that contains pyrimidine rings. Molecular and cellular studies have shown that different linkers affect the degradation activity of small-molecule degraders on the target protein of BCR-ABL. We screened out a lead compound, DMP11, with stable physicochemical properties and high activity. Preliminary evaluation of its pharmacodynamics in vitro model showed that it has a good inhibitory effect on imatinib-resistant chronic myeloid leukemia cell lines, as has been shown in animal models. Our preliminary research into the mechanism of DMP11 found that DMP11 can overcome drug resistance by simultaneously inhibiting the targets of BCR-ABL and SRC-family kinase (SFK).

PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas

“…DMP11 displayed in vivo therapeutic efficacy on imatinib-resistant-KA-induced orthotopic animal models. In this system, DMP11-treated mice showed decreased tumor progression and increased survival compared to the control group [78]. These data are consistent with previous reports demonstrating that BCR-ABL1-dependent drug resistance driven by scaffolding mechanisms may be addressed by a strategy that combines BCR-ABL1 kinase inhibition and protein degradation.…”

“…However, drug resistance can occur, and it is associated with kinase-independent and scaffolding-dependent BCR-ABL1 functions, which modulate the interaction with Shc and subsequent recruitment of GRB2 to induce survival mechanisms [79]. Degraders of BCR-ABL1 can play a role in overcoming resistance to TKIs [78,79]. The BCR-ABL1 PROTAC DMP11 significantly induced protein degradation of BCR-ABL1 as well as downstream SRC protein in vitro, thereby inhibiting cell viability of both imatinib-sensitive (K562) and imatinib-resistant (KA) chronic myeloid leukemia cell lines [78].…”

“…Degraders of BCR-ABL1 can play a role in overcoming resistance to TKIs [78,79]. The BCR-ABL1 PROTAC DMP11 significantly induced protein degradation of BCR-ABL1 as well as downstream SRC protein in vitro, thereby inhibiting cell viability of both imatinib-sensitive (K562) and imatinib-resistant (KA) chronic myeloid leukemia cell lines [78]. DMP11 displayed in vivo therapeutic efficacy on imatinib-resistant-KA-induced orthotopic animal models.…”