# Targeting Lipid Regulation Pathways by Novel Small Molecules

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $375,943

## Abstract

ABSTRACT
Cardiovascular diseases (CVD) is the number one cause of death world-wide. High levels of low density
lipoprotein (LDL), clinically known as hypercholesterolemia or hyperlipidemia, are strongly associated with
CVD. Although statin therapy has been very successful for many patients with hypercholesterolemia, about
20% of patients are not able to achieve target LDL levels due to the adverse effects of statin therapy.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major regulatory role in cholesterol homeostasis
and is a validated new therapeutic target for the treatment of hypercholesterolemia. Compounds that inhibit the
action of PCSK9 can be stand-alone treatments or function as synergistic agents with statins in a
hypercholesterolemia treatment regimen. It took only 12 years from the discovery of the PCSK9 gene to the
approval of two antibody drugs against the secreted PCSK9 protein, which is a strong testimony for the
significance and importance of PCSK9. However, the understanding of the basic biology of PCSK9 lags far
behind the clinical development. This collaborative proposal from laboratories of Tang, Attie, and Li at UW-
Madison is intended to study the biological mechanism and protein target of novel small molecules that can
lead to selective degradation of PCSK9 protein. We will accomplish these objectives by completing three
specific aims: 1) Develop sensitive assays to evaluate the potency, cytotoxicity, selectivity, and metabolic
stability of novel small molecule PCSK9 modulators; 2) Elucidate the mechanism of action of our small
molecule PCSK9 modulators by an iterative approach from transcription, translation, posttranslational
modification and degradation, to secretion; 3) Identify the direct binding partner of our small molecule PCSK9
modulators with appropriate chemical probes, investigate the physiological function of this binding partner, and
evaluate its therapeutic potential. This proposal is innovative because our small molecules target PCSK9
regulation pathways that are distinct from known biological reagents such as antibodies and known natural
products, most of which down regulate the transcription of PCSK9. Based on our preliminary results, we
hypothesize that our compounds regulate the stability of PCSK9 by selectively promoting the post-translational
degradation of PCSK9. We proposed multiple interdisciplinary approaches to examine how our small
molecules affect transcription, translation, protein processing and degradation, and the secretory pathway of
PCSK9. The proposed study will yield novel small molecule tools that can change how we study lipid regulating
pathways and also uncover new biological targets and pathways for treating hypercholesterolemia.

## Key facts

- **NIH application ID:** 9978881
- **Project number:** 5R01GM120357-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Weiping Tang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,943
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978881

## Citation

> US National Institutes of Health, RePORTER application 9978881, Targeting Lipid Regulation Pathways by Novel Small Molecules (5R01GM120357-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9978881. Licensed CC0.

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