We gratefully acknowledge financial support from Spanish Ministerio de Ciencia, Innovación y Universidades and FEDER (grants CTQ2016-76794-P, CTQ2016-80375-P and CTQ2014- 51912-REDC, and FPU-predoctoral grant to L.C.), from Consejería de Empleo, Industria y Turismo del Principado de Asturias (grant IDI/2018/000231) and from The Basque Government/ Eusko Jaurlaritza (grant IT-324-07). I.R. and F.P.C. thank the SGI/ IZO-SGIker UPV/EHU and DIPC for generous allocation of computational resources.
Altres ajuts: Suported by IKERBASQUE, Basque foundation for Science (M.J. Perugorria and J.M. Banales), Spain; "Junta de Castilla y Leon" (J.J.G. Marin: SA06P17); "Diputación Foral Gipuzkoa" (J.M. Banales: DFG15/010, DFG16/004; M.J. Perugorria: DFG18/114, DFG19/081), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales), Department of Health of the Basque Country (J.M. Banales: 2017111010; M.J. Perugorria: 2019111024), and Euskadi RIS3 (J.M. Banales: 2016222001, 2017222014, and 2018222029; 2019222054); La Caixa Scientific Foundation (J.M. Banales: HR17-00601); "Fundación Científica de la Asociación Española Contra el Cáncer" (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); and "Centro Internacional sobre el Envejecimiento", Spain (J.J.G. Marin: OLD-HEPAMARKER, 0348-CIE-6-E). A. Santos-Laso by the Basque Government (PRE_2018_2_0195), and Pui Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award). Basque Government (F.P. Cossío: IT-324-07). I. Rivilla had a postdoctoral contract from the Donostia International Physics Center. ; Background and Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their ...
