Article
作者: Fan, Yi ; Jimenez, Juan-Miguel ; Silva, Mariana ; Perez-Benito, Laura ; Vesely, Eileen ; Patrick, Aaron N. ; Nicolaï, Johan ; Van Brandt, Sven ; Wang, Yufei ; Larin, Egor M. ; Li, Siyu ; Vetrano, Irene ; Patwardhan, Gauri Anand ; Hixon, Mark S. ; Etwebi, Zienab ; Lv, Dan ; Lepri, Susan ; Last, Stefaan ; Zijlmans, Remco ; Thäte, Claudia ; Jardi, Ferran ; Jin, Shuai ; Chen, Falian ; Schepens, Wim ; Lutter, Ferdinand H. ; Mattson, Bethany ; Liddane, Alexandra G. ; Carvalho, Mary-ambre ; Silva, José ; Jiang, Zhengyu ; Yang, Jie ; Retzbach, Ed ; Hulpia, Fabian ; Fernandez Candelaria, Froylan Omar ; Everaerts, Melissa ; Gaffney, Dana ; Chu, Gerald ; Boj, Sylvia F. ; Sterckx, Hans ; Pieters, Serge ; ten Hag, Gerben ; Bush, Tammy L. ; Bachman, Kurtis E. ; Milligan, Cynthia M. ; Thuring, Jan Willem ; Francis, Albi ; Smith-Monroy, Constance ; Vinken, Petra ; Renders, Evelien ; Yao, Xuemei ; Wong, Victoria ; Verissimo, Carla S. ; Clancy, Kathleen W. ; Pocalyko, David ; Leenaerts, Joseph E. ; Verniest, Guido
Loss of the functional Adenomatous Polyposis Coli (APC-LOF) tumor suppressor gene represents the disease-initiating event in most colorectal cancer (CRC) cases. A newly identified dependency between PRMT5 and APC-LOF suggests that inhibiting PRMT5 may help intercept CRC. To circumvent hematological toxicities associated with orally bioavailable first-generation PRMT5 inhibitors, we aimed to limit systemic exposure after oral administration. We describe our efforts, challenges, and compound evaluation workflow resulting in gut-restricted PRMT5 inhibitors. A two-pronged approach was envisioned, consisting of (1) minimizing passive absorption, and (2) maximizing systemic clearance by incorporation of a metabolic "soft spot". This resulted in 9 and 18, displaying low absorption in preclinical species and high first-pass extraction mediated by aldehyde oxidase. 9 and 18 demonstrated in vivo colon pharmacodynamics without signs of systemic on-target toxicity, confirming gut-restriction. Administering 9 to dextran sodium sulfate (DSS)-treated polyp-bearing ApcMin/+ mice significantly reduced polyp number, indicating local treatment efficacy.