Summary for 9PCA
| Entry DOI | 10.2210/pdb9pca/pdb |
| Descriptor | Protein arginine N-methyltransferase 5, Methylosome protein WDR77, (1S,2R,3S,5R)-3-{2-[2-amino-6-(2-hydroxyethyl)quinolin-7-yl]ethyl}-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol, ... (6 entities in total) |
| Functional Keywords | prmt5, mep50, ligand, translocase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 112309.82 |
| Authors | |
| Primary citation | Hulpia, F.,Schepens, W.,Lepri, S.,Nicolai, J.,Jiang, Z.,Boj, S.F.,Bush, T.L.,Carvalho, M.A.,Chen, F.,Chu, G.,Clancy, K.W.,Etwebi, Z.,Everaerts, M.,Fan, Y.,Fernandez Candelaria, F.O.,Francis, A.,Hixon, M.S.,Jardi, F.,Jin, S.,Larin, E.M.,Last, S.,Leenaerts, J.E.,Li, S.,Liddane, A.G.,Lutter, F.H.,Lv, D.,Mattson, B.,Milligan, C.M.,Patrick, A.N.,Patwardhan, G.A.,Perez-Benito, L.,Pieters, S.,Renders, E.,Retzbach, E.,Smith-Monroy, C.,Silva, J.,Silva, M.,Sterckx, H.,Ten Hag, G.,Thate, C.,Van Brandt, S.,Verissimo, C.S.,Verniest, G.,Vesely, E.,Vetrano, I.,Vinken, P.,Wang, Y.,Wong, V.,Yao, X.,Yang, J.,Zijlmans, R.,Bachman, K.E.,Pocalyko, D.,Jimenez, J.M.,Gaffney, D.,Thuring, J.W. Discovery of Gut-Restricted PRMT5 Inhibitors to Intercept Colorectal Cancer in Patients with Genetic Loss of Tumor Suppressor Adenomatous Polyposis Coli. J.Med.Chem., 2025 Cited by PubMed Abstract: Loss of the functional Adenomatous Polyposis Coli (-LOF) tumor suppressor gene represents the disease-initiating event in most colorectal cancer (CRC) cases. A newly identified dependency between PRMT5 and -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 and , displaying low absorption in preclinical species and high first-pass extraction mediated by aldehyde oxidase. and demonstrated in vivo colon pharmacodynamics without signs of systemic on-target toxicity, confirming gut-restriction. Administering to dextran sodium sulfate (DSS)-treated polyp-bearing mice significantly reduced polyp number, indicating local treatment efficacy. PubMed: 40857667DOI: 10.1021/acs.jmedchem.5c00830 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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