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Identification of NUV-244 as a PNPLA3 I148M degrading small molecule
Patrick Steigemann1, Nico Braeuer1, Vera Puetter1
1Nuvisan ICB GmbH, Müllerstrasse 178, 13353 Berlin, Germany.
Abstract:
The PNPLA3 I148M variant is a key genetic determinant of metabolic dysfunction-associated steatotic liver disease (MASLD) and related conditions, contributing to lipid metabolism dysregulation and disease progression. To identify small molecules that modulate PNPLA3 I148M, we conducted a high-content screen of over 820,000 compounds and identified NUV-244, a potent degrader of PNPLA3 I148M in liver-derived cells. NUV-244 reduces PNPLA3 I148M levels on lipid droplets via the ubiquitin-proteasome system, involving the E3 ligase BFAR, without affecting PNPLA2. It restores lipid droplet morphology and improves cellular fitness in PNPLA3 I148M-expressing cells. These findings provide a tool to investigate PNPLA3 I148M function and offer a potential strategy for developing targeted therapies for MASLD and related diseases. By enabling selective degradation of PNPLA3 I148M, this approach expands therapeutic possibilities beyond genetic manipulation, addressing a critical need in metabolic liver disease research.
Insights
Researchers identified NUV-244, a compound that degrades the PNPLA3 I148M protein, a key factor in metabolic dysfunction-associated steatotic liver disease (MASLD). This discovery offers a new therapeutic strategy for MASLD.
Area of Science:
- Hepatology
- Molecular Biology
- Pharmacology
Background:
- The PNPLA3 I148M variant is a significant genetic driver of metabolic dysfunction-associated steatotic liver disease (MASLD), leading to lipid metabolism issues and disease advancement.
- Current therapeutic strategies for MASLD often lack targeted approaches for specific genetic contributors like PNPLA3 I148M.
Purpose of the Study:
- To identify small molecules capable of modulating the PNPLA3 I148M variant.
- To investigate the therapeutic potential of novel compounds in MASLD.
Main Methods:
- Conducted a high-content screen of over 820,000 compounds to find modulators of PNPLA3 I148M.
- Utilized liver-derived cell models to assess compound efficacy and mechanism of action.
- Investigated the role of the ubiquitin-proteasome system and the E3 ligase BFAR in compound-mediated degradation.
Main Results:
- Identified NUV-244 as a potent degrader of PNPLA3 I148M in liver cells.
- NUV-244 selectively reduces PNPLA3 I148M levels on lipid droplets via the ubiquitin-proteasome system, involving BFAR, without impacting PNPLA2.
- Demonstrated that NUV-244 restores normal lipid droplet morphology and enhances cellular health in cells expressing PNPLA3 I148M.
Conclusions:
- NUV-244 serves as a valuable tool for studying PNPLA3 I148M function.
- The selective degradation of PNPLA3 I148M by NUV-244 presents a promising therapeutic avenue for MASLD and related conditions.
- This approach offers a non-genetic strategy for targeting metabolic liver diseases.
