Dataset Information

A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells.

ABSTRACT: AURKA is a potential kinase target in various malignancies. The kinase-independent oncogenic functions partially disclose the inadequate efficacy of the kinase inhibitor in a Phase III clinical trial. Simultaneously targeting the catalytic and noncatalytic functions of AURKA may be a feasible approach. Here, a set of AURKA proteolysis targeting chimeras (PROTACs) are developed. The CRBN-based dAurA383 preferentially degrades the highly abundant mitotic AURKA, while cIAP-based dAurA450 degrades the lowly abundant interphase AURKA in acute myeloid leukemia (AML) cells. The proteomic and transcriptomic analyses indicate that dAurA383 triggers the "mitotic cell cycle" and "stem cell" processes, while dAurA450 inhibits the "MYC/E2F targets" and "stem cell" processes. dAurA383 and dAurA450 are combined as a PROTAC cocktail. The cocktail effectively degrades AURKA, relieves the hook effect, and synergistically inhibits AML stem cells. Furthermore, the PROTAC cocktail induces AML regression in a xenograft mouse model and primary patient blasts. These findings establish the PROTAC cocktail as a promising spatial-temporal drug administration strategy to sequentially eliminate the multifaceted functions of oncoproteins, relieve the hook effect, and prevent cancer stem cell-mediated drug resistance.

SUBMITTER: Liu F

PROVIDER: S-EPMC9353462 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells.

Liu Fang F Wang Xuan X Duan Jianli J Hou Zhijie Z Wu Zhouming Z Liu Lingling L Lei Hanqi H Huang Dan D Ren Yifei Y Wang Yue Y Li Xinyan X Zhuo Junxiao J Zhang Zijian Z He Bin B Yan Min M Yuan Huiming H Zhang Lihua L Yan Jinsong J Wen Shijun S Wang Zifeng Z Liu Quentin Q

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220602 22

AURKA is a potential kinase target in various malignancies. The kinase-independent oncogenic functions partially disclose the inadequate efficacy of the kinase inhibitor in a Phase III clinical trial. Simultaneously targeting the catalytic and noncatalytic functions of AURKA may be a feasible approach. Here, a set of AURKA proteolysis targeting chimeras (PROTACs) are developed. The CRBN-based dAurA383 preferentially degrades the highly abundant mitotic AURKA, while cIAP-based dAurA450 degrades t ...[more]

PMID: 35652200

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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

A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells.

Publications

A Temporal PROTAC Cocktail-Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells.

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