# Utilizing the HiBiT System to Identify CARM1 Degraders for Targeted Cancer Therapy

## TL;DR

Researchers used a new screening method to find natural compounds that can degrade CARM1, a protein linked to breast cancer, offering potential new cancer treatments.

## Contribution

A high-throughput screening platform using the HiBiT system was developed to identify natural CARM1 degraders with drug-like properties.

## Key findings

- Two natural compounds, kusunokinin and exostemin, were identified as specific CARM1 degraders.
- Both compounds inhibited breast cancer cell colony formation and migration.
- The compounds showed selectivity over other protein arginine methyltransferases.

## Abstract

Preclinical studies validated coactivator-associated
arginine methyltransferase
1 (CARM1) as a targetable therapeutic vulnerability, leading to the
development of Proteolysis-Targeting Chimeras that specifically degrade
CARM1. These compounds face significant translational challenges,
including poor oral bioavailability and limited metabolic stability,
which require extensive optimization. To identify more drug-like CARM1
degraders, we developed a high-throughput screening platform. We enabled
antibody-free monitoring of CARM1 levels by fusing a HiBiT tag to
CARM1 in MCF7 breast cancer cells. Complementation with LgBiT produces
luciferase activity. Using this platform, we screened 1408 plant-derived
natural product fractions to identify compounds that reduce CARM1
protein levels. This screen revealed two promising natural compounds,
kusunokinin and exostemin, that specifically target CARM1 for degradation
with selectivity over other protein arginine methyltransferases. Both
compounds demonstrated functional anticancer activity, significantly
inhibiting breast cancer cell colony formation and migration. Kusunokinin
and exostemin represent lead compounds for developing next-generation
CARM1-targeted therapeutics with enhanced translational potential.