Project description:Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in cancers, encodes a chromatin modulator and an attractive onco-target. However, agent that can effectively suppress the NSD3-mediated oncogenic actions is currently lacking. We report an NSD3-targeting proteolysis targeting chimera (PROTAC), termed MS9715, which achieves effective and specific depletion of NSD3 and interacting partners (including cMyc) in tumor cells. MS9715-induced NSD3 degradation relies on BI-9321, an antagonist module binding the PWWP1 domain of NSD3, and VHL, which is chemically conjugated to BI-9321 via a linker and VHL ligand module. Importantly, compared to BI-9321, a recently disclosed NSD3 antagonist, MS9715 is more potent in suppressing growth of the NSD3-dependent hematological cancer including models of MLL-rearranged acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL) and multiple myeloma (MM), and uniquely mediate simultaneous depletion of cellular NSD3 and cMyc. Transcriptome profiling further demonstrates effective actions of MS9715 but not BI-9321 in suppressing both NSD3- and cMyc-associated gene-expression programs, a phenomenon reminiscent of the CRISPR/cas9-mediated knockout (KO) of NSD3. Together, this study reports a first-in-class NSD3 PROTAC/degrader suitable for co-suppressing NSD3- and cMyc-related oncogenic nodes in cancer cells, suggesting a novel therapeutic strategy.

2021-08-27 | PXD021901 | Pride

Caproicibacterium lactatifermentans

Project description:Caproicibacterium lactatifermentans overview

| PRJNA803575 | ENA

Caproicibacterium amylolyticum

Project description:Caproicibacterium amylolyticum overview

| PRJNA1181083 | ENA

An NSD3-targeting PROTAC (Proteolysis Targeting Chimeric) suppresses the NSD3 and cMyc oncogenic nodes in cancer cells

Project description:Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in human cancers, encodes a chromatin modulator and an attractive onco-target. However, agent that can effectively suppress the NSD3-mediated oncogenic actions is currently lacking. Here, we report an NSD3-targeting proteolysis targeting chimera (PROTAC), termed MS9715, which achieves effective and specific depletion of NSD3 and interacting partners (including cMyc) in tumor cells. We show that MS9715-induced NSD3 degradation relies on BI-9321, an antagonist module binding the PWWP1 domain of NSD3, and VHL, which is chemically conjugated to BI-9321 via a linker and a VHL ligand. Importantly, compared to BI-9321, a recently disclosed NSD3 antagonist, MS9715 is more potent in suppressing growth of the NSD3-dependent hematological cancer including models of MLL-rearranged acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL) and multiple myeloma (MM), and uniquely mediates simultaneous depletion of cellular NSD3 and cMyc. Transcriptome profiling further demonstrates effective actions of MS9715 but not BI-9321 in suppressing both the NSD3- and cMyc-mediated gene-expression programs, a phenomenon reminiscent of the CRISPR/cas9-mediated knockout (KO) of NSD3. Together, this study reports a first-in-class NSD3 degrader suitable for co-suppressing NSD3- and cMyc-related oncogenic nodes in cancer, suggesting a novel therapeutic strategy,

2021-08-31 | GSE158296 | GEO

NSD3-short is an adaptor protein that couples BRD4 to the CHD8 chromatin remodeler (ChIP-Seq)

Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. ChIP-Seq for regulatory factors of BRD4, NSD3, CHD8 and histone modification H3K36me2 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)

2015-12-17 | E-GEOD-71183 | biostudies-arrayexpress

Caproicibacterium amylolyticum strain:LBM18003

Project description:Caproicibacterium amylolyticum strain:LBM18003 Genome sequencing

| PRJNA656405 | ENA