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

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-1a 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-1a/MEF-2-dependent adaptive survival signaling in the compromised TME found in mCRPC. Overall design: RNA sequencing of prostate tumor patient-derived xenograft (PDX) models using Illumina TruSeq Library prep and sequenced on Illumina NovaSeq 6000.