Table 3.

Summary of Drug Screening Studies (zebrafish)

Model(s)	Gene	Disease	Study Design	Drug/Target Identified	Results	Ref(s)
Drug screening studies
pkd2−/− (hi4166), ift172−/− (hi2211), and pkd2 morphants	pkd2 and ift172	ADPKD, and retinitis pigmentosa and short-rib thoracic dysplasia	Chemical modifier drug screen with a custom library of 115 compounds (cell cycle progression, apoptosis, actin and microtubule cytoskeleton, calcium signaling, vesicular trafficking, receptor tyrosine kinase pathways, posttranslational modifications, protein degradation, and chromatin remodeling)	HDAC inhibition	HDAC inhibition with TSA and VPA corrected body curvature (pkd2−/− [hi4166]) and reduced cyst formation (pkd2 morphants) in zebrafish; results verified by treating Pkd1fl/fl, Pkhd1-cre mice with VPA (reduced %KW/BW, CI, and BUN)	63
pkd2−/− (hu2173)	pkd2	ADPKD	Unbiased chemical screen using two publicly available compound libraries (spectrum, PKIS; 2367 compounds total)	ALK5 (TGFβR1) and noncanonical androgen receptors	Treatment with several steroids, coumarins, and flavonoids (spectrum library) exacerbated PKD phenotypes in pkd2−/− zebrafish (tail curvature), and androgen and 5α-androstane 3,17-dione had the strongest effect (independent of canonical androgen signaling). Whereas, treatment with several ALK5 (TGFβR1) kinase inhibitors (PKIS library; diclofenac, dibutylhydroxyanisole, and zinc pyrithione) partially ameliorated PKD phenotypes (tail curvature) in pkd2−/− zebrafish, ultimately validated with the ALK5 inhibitor, SD208. Results verified in 3D cyst cultures	115

ADPKD, autosomal dominant polycystic kidney disease; HDAC, histone deacetylase; TSA, trichostatin A, VPA, valproic acid; %KW/BW, percentage kidney weight/body weight; CI, cystic index; BUN, blood urea nitrogen; PKIS, published kinase inhibitor set; PKD, polycystic kidney disease.