In silico Modeling for Small Molecule PRMT6 Inhibitors for the Treatment of Spinal Bulbar Muscular Atrophy (SBMA)

Spinal Bulbar Muscular Atrophy (SBMA), or Kennedy’s disease, is a rare, inherited neuromuscular disorder that leads to progressive muscle degeneration, weakness, and twitching. While it affects approximately 1 in 100,000 individuals worldwide, currently, there are no approved treatments for SBMA, leaving a substantial unmet medical need. 

Our program focuses on developing a novel therapeutic approach targeting PRMT6, a co-activator of the Androgen Receptor (AR) implicated in SBMA progression. The aim is to design a highly selective, brain-penetrant PRMT6 inhibitor targeting an allosteric site on the enzyme. Preliminary studies have shown that inhibiting PRMT6 reduces mutant AR activity and improves motor function in disease models. 

Here, we employ AI-guided in silico modeling to optimize the PRMT6 probe scaffold SGC6870 as a potential therapeutic for the treatment of  SBMA. This workflow integrates computational drug design, medicinal chemistry, and molecular biology, with subsequent in vitro and in vivo ADME optimization of prioritized compounds.

Table of key terms and definitions:

Key term

Definition 

PRMT6

Protein arginine methyltransferase 6, a transcriptional co-regulator

Androgen receptor (AR)

Type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in the cytoplasm and then translocating into the nucleus

SBMA 

X-linked, slowly progressive neuromuscular disorder that affects adult males, typically presenting with muscle weakness, bulbar dysfunction, and endocrine abnormalities

SGC6870

A potent, selective and cell active allosteric inhibitor of PRMT6

S-adenosyl-L-methionine (SAM)

Methyltransferase cofactor

SAR

Structure activity relationship

ADME

Absorption, Distribution, Metabolism and Excretion

DMPK

Drug metabolism and pharmacokinetics