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

Xu Zhang; Linglan Tu; Haohuan Chai; Zilin Li; Yuhan Fu; Xiaoliang Zheng; Shenxin Zeng; Liyan Cheng

doi:10.1155/2022/4056398

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

J Oncol. 2022 Oct 30:2022:4056398. doi: 10.1155/2022/4056398. eCollection 2022.

Authors

Xu Zhang¹, Linglan Tu¹, Haohuan Chai¹, Zilin Li¹, Yuhan Fu¹, Xiaoliang Zheng^{1

2}, Shenxin Zeng³, Liyan Cheng^{1

2}

Affiliations

¹ School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, China.
² Zhejiang Provincial Laboratory of Experimental Animal's and Nonclinical Laboratory Studies, Hangzhou, Zhejiang, China.
³ School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China.

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).