Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity.

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 in vivo lead compound, 28 ("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 in vivo efficacy in several MTAP-deficient preclinical cancer models.

The relative function of damaged kidneys in children does not deteriorate further at 3-year follow-up.

PURPOSE: It is thought that the function of a damaged kidney will deteriorate further with time because of impaired maturation and compensatory hyperfiltration. The aim of this study was to determine changes in relative renal function (RRF) over time in children with vesicoureteric reflux (VUR) and/or urinary tract infection (UTI) where the unilaterally scarred kidney was found to contribute 30% or less to overall function. PATIENTS AND METHODS: Children who met the inclusion criteria and had multiple radionuclide studies during a 12-year period were identified, and RRF was compared. RESULTS: Twenty-seven boys and 3 girls with a median age of 0.8 years (0.08-13.05 years) were included. Eight patients had unilateral VUR, 21 patients had bilateral VUR, and 1 patient had UTIs without VUR. Twenty-one patients underwent reimplantation surgery, and 9 were managed conservatively.At a mean follow-up of 2.64 years (0.26-6.77 years), there was a nonsignificant mean decrease in RRF from 19% (11%-28%) to 18% (9%-29%). The mean change in renal function was not affected by the severity of the initial RRF. CONCLUSIONS: In the medium term, there is no deterioration of RRF of unilaterally severely damaged kidneys associated with either VUR or UTI managed either surgically or conservatively. Boys are at a much greater risk of severe reflux nephropathy.