9EYW

Human PRMT5 in complex with AZ compound 21

This is a non-PDB format compatible entry.

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

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: 39080842
DOI: 10.1021/acs.jmedchem.4c00097

Experimental method

X-RAY DIFFRACTION (2.3 Å)