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The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination.

ABSTRACT: Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides promising substitutions for E3 ubiquitin ligase complex-mediated ubiquitination of "undruggable proteins". It is worth noting that successful applications of p-PROTAC still have some obstacles, including low stability and poor membrane permeability. Hence, we highlight that p-PROTAC combined with cell-penetrating peptides, constrained conformation technique, and targeted delivery systems could be the future efforts for potential translational research.

SUBMITTER: Jin J

PROVIDER: S-EPMC7481416 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination.

Jin Jinmei J Wu Ye Y Chen Jinjiao J Shen Yiwen Y Zhang Lijun L Zhang Hong H Chen Lili L Yuan Hebao H Chen Hongzhuan H Zhang Weidong W Luan Xin X

Theranostics 20200808 22

Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides ...[more]

PMID: 32929339

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Project description:Although the use of ATP-competitive tyrosine kinase inhibitors of oncoprotein BCR-ABL1 has enabled durable responses in patients with chronic myeloid leukemia (CML), issues of drug resistance and residual leukemic stem cells remain. To test whether the degradation of BCR-ABL1 kinase could offer improved response, we developed a series of proteolysis-targeting chimera (PROTAC) that allosterically target BCR-ABL1 protein and recruit the E3 ligase Von Hippel-Lindau, resulting in ubiquitination and subsequent degradation of the oncogenic fusion protein. In both human CML K562 cells and murine Ba/F3 cells expressing BCR-ABL1, lead compound GMB-475 induced rapid proteasomal degradation and inhibition of downstream biomarkers, such as STAT5, and showed increased sensitivity compared with diastereomeric controls lacking degradation activity. Notably, GMB-475 inhibited the proliferation of certain clinically relevant BCR-ABL1 kinase domain point mutants and further sensitized Ba/F3 BCR-ABL1 cells to inhibition by imatinib, while demonstrating no toxicity toward Ba/F3 parental cells. Reverse phase protein array analysis suggested additional differences in levels of phosphorylated SHP2, GAB2, and SHC associated with BCR-ABL1 degradation. Importantly, GMB-475 reduced viability and increased apoptosis in primary CML CD34+ cells, with no effect on healthy CD34+ cells at identical concentrations. GMB-475 degraded BCR-ABL1 and reduced cell viability in primary CML stem cells. Together, these findings suggest that combined BCR-ABL1 kinase inhibition and protein degradation may represent a strategy to address BCR-ABL1-dependent drug resistance, and warrant further investigation into the eradication of persistent leukemic stem cells, which rely on neither the presence nor the activity of the BCR-ABL1 protein for survival. SIGNIFICANCE: Small-molecule-induced degradation of BCR-ABL1 in CML provides an advantage over inhibition and provides insights into CML stem cell biology. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/18/4744/F1.large.jpg.

Dataset Information

The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination.

Publications

The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination.

Similar Datasets

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