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Third Generation Quinoline-3-Carboxamide Transcriptional Disrupter of HDAC4, HIF-1α, and MEF-2 Signaling for Metastatic Castration-Resistant Prostate Cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211375 | GEO | 2023/08/11

REPOSITORIES: GEO

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Project description:Mitochondria are subcellular organelles that are more than just the powerhouse of cells, they also dictate if a cell dies or survives. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) has been shown to play a crucial role in metabolism and apoptosis, however its involvement in ischemic pathologies and cancer is not clear. Transcriptome analysis of Vdac1-/- mouse embryonic fibroblasts (MEF) highlighted cancer and inflammation as top diesases but also activation of the HIF-1 signaling pathway in normoxia. HIF-1α protein was stable due to ROS accumulation that decreased respiration and glycolysis and maintained basal apoptosis. However, in hypoxia increased activation of ERK in combination with maintenance of respiration and increased glycolysis counterbalanced the deleterious effects of ROS, thereby allowing Vdac1-/- MEF to proliferate better than wild-type MEF. Xenografts of RAS-transformed Vdac1-/- MEF in mice showed stabilization of both HIF-1α and HIF-2α which led to blood vessel destabilization and a strong inflammatory response. Moreover, expression of Cdkn2a, a HIF-1-target and tumor suppressor gene, was strongly decreased. Consequently RAS-transformed Vdac1-/- MEF tumors grew faster than wild-type MEF tumors. These findings provide new perspectives into the understanding of VDAC1 in the function of mitochondria not only in cancer but also in inflammatory diseases. Profiling of VDAC1-/- and wild-type (Wt) Mouse Embryonic Fibroblasts (MEFs) was performed using whole genome mouse microarrays. in normoxic or hypoxic conditions. MEF (Wt and Vdac1-/-) were incubated in normoxia (Nx, ie: 20% O2) or hypoxia (Hx, ie: 1% O2) for 72h and then lysed prior to RNA isolation, labelling and hybridization on microarrays. One color experiment with 2 biological replicates (marked 1 or 2) of the 4 experimental conditions. One condition (MEF WT Nx2) has been removed from the statistical analysis after microarray quality check due to high background. Total of 7 samples.

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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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