# Small molecule allosteric inhibitors of PCSK9 processing to phenocopy cardioprotective genetic variants.

> **NIH NIH R61** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $537,538

## Abstract

PROJECT SUMMARY/ABSTRACT
The self-cleaving protease PCSK9 induces the lysosomal degradation of the hepatic low-density lipoprotein
receptor (LDLR). Thus, PCSK9 raises serum LDL and promotes atherosclerotic heart disease. Human
genetics show that secreted PCSK9 is dispensable, making PCSK9 an important drug target. Both therapeutic
anti-PCSK9 antibodies and liver-specific anti-PCSK9 siRNA impressively lower LDL and improve
cardiovascular outcomes, even when added on top of statins. Yet despite this clinical success, problems
remain. First, the role of PCSK9 beyond downregulating the hepatic LDLR remains unclear, and so there are
gaps in the knowledge of the site effects from or other indications for the current available therapies. Second,
currently approved therapies are not orally available, expensive, and poorly covered by insurance (antibodies),
or phenocopy genetic models that associate with liver disease (siRNA).
In this proposal, we target a novel mechanism for PCSK9 inhibition: the disruption of PCSK9 processing.
PCSK9 is a self-cleaving protease, and this auto-proteolysis is required for its secretion and full effect on the
LDLR. However, because PCSK9’s cleavage is both intramolecular and terminal, no other group has
discovered how to disrupt it. Our group, however, has solved this problem, and we have discovered a series of
molecules that allosterically modulate PCSK9 proteolysis to disrupt PCSK9 function. Importantly, this
mechanism phenocopies the well-tolerated human PCSK9 variants who have no adverse phenotypes, only
lower LDL and cardiovascular protection. In the R61 phase of this proposal, we will pursue a medicinal
chemistry campaign to identify, validate, and screen compounds for activity. We will generate a diversity library
to establish novel intellectual property, confirm target engagement with PCSK9, and improve the efficacy,
potency, and pharmacologic properties of our compounds. In the R33 phase, we will establish in vivo efficacy
and pharmacologically validate a developmental candidate to identify a lead compound for IND-enabling
studies. We anticipate that our proposal will have a high impact on cardiovascular disease by enabling the
development of an oral small molecule inhibitor of PCSK9 that truly phenocopies the cardioprotective genetic
variants found in humans.

## Key facts

- **NIH application ID:** 10747623
- **Project number:** 1R61HL170383-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** John S Chorba
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $537,538
- **Award type:** 1
- **Project period:** 2023-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747623

## Citation

> US National Institutes of Health, RePORTER application 10747623, Small molecule allosteric inhibitors of PCSK9 processing to phenocopy cardioprotective genetic variants. (1R61HL170383-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10747623. Licensed CC0.

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