Summary for 9EYW
| Entry DOI | 10.2210/pdb9eyw/pdb |
| Descriptor | Protein arginine N-methyltransferase 5, N-terminally processed, Methylosome protein WDR77, (3~{S})-2-[(5-azanyl-1~{H}-pyrrolo[3,2-b]pyridin-2-yl)methyl]-6-fluoranyl-1'-[(4-fluorophenyl)methyl]spiro[isoindole-3,3'-pyrrolidine]-1,2'-dione, ... (6 entities in total) |
| Functional Keywords | methyl transferase, inhibitor, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 110390.78 |
| Authors | Debreczeni, J. (deposition date: 2024-04-09, release date: 2024-08-14, Last modification date: 2024-09-04) |
| Primary citation | Smith, J.M.,Barlaam, B.,Beattie, D.,Bradshaw, L.,Chan, H.M.,Chiarparin, E.,Collingwood, O.,Cooke, S.L.,Cronin, A.,Cumming, I.,Dean, E.,Debreczeni, J.E.,Del Barco Barrantes, I.,Diene, C.,Gianni, D.,Guerot, C.,Guo, X.,Guven, S.,Hayhow, T.G.,Hong, T.,Kemmitt, P.D.,Lamont, G.M.,Lamont, S.,Lynch, J.T.,McWilliams, L.,Moore, S.,Raubo, P.,Robb, G.R.,Robinson, J.,Scott, J.S.,Srinivasan, B.,Steward, O.,Stubbs, C.J.,Syson, K.,Tan, L.,Turner, O.,Underwood, E.,Urosevic, J.,Vazquez-Chantada, M.,Whittaker, A.L.,Wilson, D.M.,Winter-Holt, J.J. Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity. J.Med.Chem., 67:13604-13638, 2024 Cited by PubMed Abstract: PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available lead compound, ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven efficacy in several MTAP-deficient preclinical cancer models. PubMed: 39080842DOI: 10.1021/acs.jmedchem.4c00097 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
Download full validation report
