Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disease, with an estimated prevalence of between one in 1000 and one in 2500 individuals.(1), (2) ADPKD is characterized by progressive cyst formation/expansion originating from renal collecting ducts, leading to enlarged kidneys and declined kidney function.3 Approximately half of ADPKD patients will progress into end-stage kidney disease in their fifth to sixth decade of life due to the continuous loss of kidney function. Most patients have to resort to dialysis or opt for kidney transplantation eventually.4 Despite considerable advances, the array of therapeutic options for ADPKD remains sparse. Currently, tolvaptan (TVP) stands alone as the sole FDA-approved medication for those afflicted with rapidly progressive ADPKD. However, its use is reported with notable adverse reactions, most prominently hepatotoxicity.(5), (6), (7) Therefore, alternative therapeutic methods for ADPKD are urgently needed.

Numerous scientific investigations indicate that the epigenetic modulation of gene expression and protein functions plays an important role in the process of cyst growth of ADPKD.8 One of the epigenetic modifiers, histone deacetylases (HDACs) are critical negative regulators of PKD genes and/or the signalling pathways that are involved in cystogenesis.(8), (9), (10), (11), (12), (13), (14) For instance, HDAC1 orchestrates renal cystic epithelial cell proliferation via the Id2-regulated p21 or alternative Rb-E2F pathways.9 Other studies found that HDAC6 protein expression or its enzyme activity is aberrantly upregulated in Pkd1 mutant renal epithelial cells.10 This upregulation drives cystic epithelial cell proliferation and excessive fluid secretion.(11), (12) Furthermore, pharmacological inhibition of HDAC activities by pan-HDAC inhibitors (e.g., SAHA, trichostatin A and valproic acid, Figure 1) can slow down the progression of cyst formation and the decline of kidney function in a mouse model of ADPKD.(13), (14) Therefore, the development of potential HDAC inhibitors may have therapeutic benefits in the treatment of ADPKD.

The pharmacophore model of existing HDAC inhibitors normally consists of three structural features (Figure 1, upper panel): (i) a zinc-binding group (ZBG) chelating with the central zinc ion, (ii) a linker passing through the hydrophobic ion channel, and (iii) a surface recognition region (head group) interacting with the amino acid residues on the rim of the catalytic tunnel.15 Recent research reported that compound 9k bearing benzimidazole ring not only improved HDAC inhibitory activities compared to SAHA but also exhibited potent antiproliferation activities against tumor cells.16 Compound XP5 bearing phenylthiazole ring displayed high antiproliferative activity against various cancer cell lines due to its potent HDAC6 inhibitory activity.17 To expand the chemical space for potential HDAC inhibitors, we substituted the benzimidazole moiety in compound 9k with a bioisosteric benzothiazole (a thiazole-fused phenyl ring) at the surface recognition site. Further chemical modifications were introduced as follows: (1) introducing a large hydrophobic group (benzothiazole ring) in the surface recognition region; (2) varying the length and the position of the linker between the surface recognition region and zinc-binding group; (3) keeping the hydroxamic acid-based zinc-binding domain (Figure 1). A series of benzothiazole derivatives were designed and synthesized as new structured HDAC inhibitors. The selected compound was advanced for comprehensive pharmacological characterization in in vitro, ex vivo, and in vivo models of ADPKD.