10 research outputs found
Multi-disciplinary efforts to evaluate the therapeutic potential of CDK11, a novel transcription associated cyclin dependent kinase.
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PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.
Statement of significance
PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors
Development of novel cellular histone-binding and chromatin-displacement assays for bromodomain drug discovery
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Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor
The bromodomain containing proteins
TRIM24 (tripartite motif containing
protein 24) and BRPF1 (bromodomain and PHD finger containing protein
1) are involved in the epigenetic regulation of gene expression and
have been implicated in human cancer. Overexpression of TRIM24 correlates
with poor patient prognosis, and BRPF1 is a scaffolding protein required
for the assembly of histone acetyltransferase complexes, where the
gene of MOZ (monocytic leukemia zinc finger protein) was first identified
as a recurrent fusion partner in leukemia patients (8p11 chromosomal
rearrangements). Here, we present the structure guided development
of a series of <i>N</i>,<i>N</i>-dimethylbenzimidazolone
bromodomain inhibitors through the iterative use of X-ray cocrystal
structures. A unique binding mode enabled the design of a potent and
selective inhibitor <b>8i</b> (IACS-9571) with low nanomolar
affinities for TRIM24 and BRPF1 (ITC <i>K</i><sub>d</sub> = 31 nM and ITC <i>K</i><sub>d</sub> = 14 nM, respectively).
With its excellent cellular potency (EC<sub>50</sub> = 50 nM) and
favorable pharmacokinetic properties (<i>F</i> = 29%), <b>8i</b> is a high-quality chemical probe for the evaluation of
TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo
MOESM1 of Development of novel cellular histone-binding and chromatin-displacement assays for bromodomain drug discovery
Additional file 1. Six supplementary figures and three supplementary tables
PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.Statement of significancePDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors
Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2
An inhibitor of oxidative phosphorylation exploits cancer vulnerability
Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors