Third Generation Quinoline-3-Carboxamide Transcriptional Disrupter of HDAC4, HIF-1α, and MEF-2 Signaling for Metastatic Castration-Resistant Prostate Cancer
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ABSTRACT:
PROVIDER: PRJNA870064 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21088025_1.fastq.gz | Fastqsanger.gz | |||
| SRR21088025_2.fastq.gz | Fastqsanger.gz | |||
| SRR21088026_1.fastq.gz | Fastqsanger.gz | |||
| SRR21088026_2.fastq.gz | Fastqsanger.gz | |||
| SRR21088027_1.fastq.gz | Fastqsanger.gz |
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Project description:The quinoline-3-carboxamide, Tasquinimod, is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor microenvironment (TME). In phase 3 clinical testing against metastatic castration-resistant prostate cancer (mCRPC), Tasquinimod (1 mg/day) increased time-to-progression, but not overall survival. Here, we document that, on this regimen, blood levels are 10-fold lower than the optimal concentration (≥2 μM) needed for anti-cancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that Tasquinimod is an aryl hydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1 μM to produce unwanted off-target side effects. Therefore, we screened a library of Tasquinimod analogs to maximize on-target vs. off-target activity. Using this approach, we identified ESATA-20, which has ~10-fold lower AHR agonism and >5-fold greater potency against prostate cancer patient-derived xenografts. This increased therapeutic index nominates ESATA-20 as a lead candidate for clinical development as an orally active 3rd generation quinoline-3-carboxamide analog that retains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromised TME found in mCRPC.
2023-08-11 | GSE211375 | GEO
Project description:BackgroundThe quinoline-3-carboxamide, Tasquinimod (TasQ), is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor micro environment. In phase 3 clinical testing against metastatic castration-resistant prostate cancer(mCRPC), TasQ (1 mg/day) increased time-to-progression, but not overall survival.MethodsTasQ analogs were chemically synthesized and tested for activity compared to the parental compound. These included HDAC4 enzymatic assays, qRT-PCR and western blot analyses of gene and protein expression following treatment, in vitro and in vivo efficacy against multiple prostate cancer models including PDXs, pharmacokinetic analyses,AHR binding and agonist assays, SPR analyses of binding to HDAC4 and NCoR1, RNAseq analysis of in vivo tumors, 3D endothelial sprouting assays, and a targeted kinase screen. Genetic knockout or knockdown controls were used when appropriate.ResultsHere, we document that, on this regimen (1 mg/day), TasQ blood levels are 10-fold lower than the optimal concentration (≥2 μM) needed for anticancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that TasQ is an arylhydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1 μM to produce unwanted off-target side effects. Therefore, we screened a library of TasQ analogsto maximize on-target versus off-target activity. Using this approach, we identified ESATA-20, which has ~10-fold lower AHR agonism and 5-fold greater potency against prostate cancer patient-derived xenografts.ConclusionThis increased therapeuticindex nominates ESATA-20 as a lead candidate forclinical development as an orally active third generation quinoline-3-carboxamide analog thatretains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromisedtumor microenvironment found in mCRPC.
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Project description:Access to DNA is the first level of control in regulating gene transcription, a control that is also critical for maintaining DNA integrity. Cellular senescence is characterized by profound transcriptional rearrangements and accumulation of DNA lesions. Here, we discovered an epigenetic complex between HDAC4 and HDAC1/HDAC2 that is involved in the erase of H2BK120 acetylation. The HDAC4/HDAC1/HDAC2 complex modulates the efficiency of DNA repair by homologous recombination, through dynamic deacetylation of H2BK120. Deficiency of HDAC4 leads to accumulation of H2BK120ac, impaired recruitment of BRCA1 and CtIP to the site of lesions, accumulation of damaged DNA and senescence. In senescent cells this complex is disassembled because of increased proteasomal degradation of HDAC4. Forced expression of HDAC4 during RAS-induced senescence reduces the genomic spread of γH2AX and affects H2BK120ac levels, which are increased in DNA-damaged regions accumulated during RAS-induced senescence. In summary, degradation of HDAC4 during senescence causes the accumulation of damaged DNA and contributes to the activation of the transcriptional program controlled by super-enhancers that maintains senescence.
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Project description:Transcriptional alterations are characteristic of persistent pain states but the key regulators remain elusive. Using a conditional knockout (cKO) strategy in mice we sought to determine whether loss of the transcriptional co-repressor histone deacetylase four (HDAC4) would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely dispensable for transcriptional regulation of naïve sensory neurons but was required for transcriptional responses after injury, with Calca and Trpv1 expression consistently downregulated in HDAC4 cKO compared to littermate controls (0.2-0.44 fold). This downregulation corresponded to reduced sensitivity to capsaicin in vitro (76% +/- 4.4% wildtype capsaicin responders vs 56.9% +/- 4.7% cKO responders) and to reduced thermal hypersensitivity in the complete Freund’s adjuvant model of inflammatory pain (1.3-1.4 fold improvement). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors. Total RNA was extracted from HDAC4 cKO and HDAC4 fl/fl naïve adult lumbar dorsal root ganglia (n=3/group). mRNA expression was compared using Affymetrix Mouse Gene Arrays (Mouse Gene 2.0ST) run on a GeneChip Fluidics Station 450. Chips were scanned on an Affymetrix GeneChip Scanner.
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Project description:To explore the downstream genes of HDAC4, we performed RNA-seq to screen after knocking down HDAC4 in 5-8F cells, a nasopharyngeal carcinoma cell line.
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Project description:The quinoline-3-carboxamide ABR-215050 (Tasquinimod (INN)), exhibits anti-tumor activity via inhibition of tumor angiogenesis in human and rodent tumors. To further explore the mode of action of ABR-215050, in vivo experiments with gene microarray analysis were performed using samples of LNCaP prostate tumors excised from nude mice exposed to ABR-215050 for 24h at 10 mg/kg(ad.lib.). The array data were validated by real-time PCR (sqRT-PCR), as well as by protein expression experiments. Among several significant differentially expressed gene after exposure to ABR-215050, were cytokine receptor CXCR4, cytochrome P450 1A1 (CYP1A1), thrombospondin-1 (THBS1) and Lysyloxidase preprotein (LOX). To further explore the mode of action of ABR-215050, in vitro experiments with gene microarray analysis were performed using LNCaP prostate tumor cells. The array data were validated by real-time PCR (sqRT-PCR), as well as by protein expression experiments. One of the most significant differentially expressed genes after exposure to ABR-215050, was thrombospondin-1 (THBS1).
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Project description:Transcriptional alterations are characteristic of persistent pain states but the key regulators remain elusive. Using a conditional knockout (cKO) strategy in mice we sought to determine whether loss of the transcriptional co-repressor histone deacetylase four (HDAC4) would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely dispensable for transcriptional regulation of naïve sensory neurons but was required for transcriptional responses after injury, with Calca and Trpv1 expression consistently downregulated in HDAC4 cKO compared to littermate controls (0.2-0.44 fold). This downregulation corresponded to reduced sensitivity to capsaicin in vitro (76% +/- 4.4% wildtype capsaicin responders vs 56.9% +/- 4.7% cKO responders) and to reduced thermal hypersensitivity in the complete Freund’s adjuvant model of inflammatory pain (1.3-1.4 fold improvement). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors.
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Project description:HDACs play crucial role in epigenetic modulation through deacetylation of histone and non-histone substrates in critical process of normal development and cancer. Moreover, HDAC inhibitors have been considered as new agent by effects such as cell cycle arrest, apoptosis, anti-angiogenic effects and autophagy and utilized in clinical applications for chemotherapy. we previously reported that HDAC 1, 4, 6 and 8 were higly expressed in MDA-MB-231 than MCF-7 cells and HDAC1, 6 and 8 excepting HDAC4 were associated with invasion that is very important factor in cancer progression. However, HDAC4 did not affect in invasion. To investigate interaction between chemoresistance and HDAC4 expression, we establish stable cells overexpressing HDAC4 in MCF-7 cells. Cells overexpressed HDAC4 were increased cytotoxicity about 5-FU and identified 356 differentially expressed genes using Ilumina array. Based on array result, we selected SMAD4 as a candidate gene related with chemoresistance because SMAD4 was previously reported evaluation of chemoresistance to 5-FU. We purpose that HDAC4 regulated with SMAD4 expression through acetylation in SMAD4 promoter region. HDAC4 directly bound a part of SMAD4 promoter. Total RNA obtained from cells overexpressed HDAC4 cDNA in MCF-7 compared to control cells.
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