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Development of a SIN1 targeting inhibitor as a novel therapeutic approach for the treatment of malignancies

ABSTRACT: We have developed a novel mTOR pathway inhibitor via targeting SIN1. We used multiple proteomics analyses to determine mechanism of action of our novel Sin1 inhibitor and compare to other mTOR pathway inhibitors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukemia Cell

DISEASE(S): Leukemia

SUBMITTER: Michael Caldwell

LAB HEAD: Leonidas Platanias

PROVIDER: PXD040952 | Pride | 2026-01-26

REPOSITORIES: Pride

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			Action	DRS
	20210820_vcs075_21-2659_Platanias_Beauchamp_01-Control-1_H1.raw	Raw
	20210820_vcs075_21-2659_Platanias_Beauchamp_01-Control-1_H2.raw	Raw
	20210820_vcs075_21-2659_Platanias_Beauchamp_01-Control-1_H3.raw	Raw
	20210820_vcs075_21-2659_Platanias_Beauchamp_01-Control-1_H4.raw	Raw
	20210820_vcs075_21-2659_Platanias_Beauchamp_02-rapamycin-1_H1.raw	Raw

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A cell competition-based drug screen identifies a novel compound that induces dual c-Myc degradation and p53 activation

Project description:BCR-Abl is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells. Leukemic stem cells are cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. Using BCR-Abl as a model oncogene, we performed a drug screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells, and identified several compounds that selectively target BCR-Abl-transformed cells. Systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. c-Myc depletion occurred in a wide range of tumor types, including leukemia, lymphoma, lung, glioblastoma and breast cancer. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest and cell differentiation, and primary leukemic stem cells were particularly sensitive to DJ34. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against leukemic stem cells.

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Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays - Revisions

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