# High-throughput discovery platform for modulators of cardiac muscle proteins to treat heart failure

> **NIH NIH R43** · PHOTONIC PHARMA, LLC · 2022 · $306,471

## Abstract

Project Summary
This Phase I SBIR collaboration between Photonic Pharma LLC (PP) and the University of Arizona (UA)
will establish proof-of-concept for an innovative drug-discovery campaign for treatment of heart failure (HF),
targeting cardiac myosin-binding protein C (MyBP-C). There is an urgent need for novel therapies for HF, a
major health problem affecting 1 in 30 adults in the US. MyBP-C has been identified as a therapeutic target for
correcting HF. Phosphorylation affects N-terminal MyBP-C structure, affecting its binding to actin and myosin,
modulating contraction and relaxation. Therefore, targeting MyBP-C with drugs that mimic phosphorylation
and/or modulate its binding to actin or myosin is a promising approach to treatment of heart failure. PP has
developed patented technology for fluorescent protein biosensors and high-throughput screening (HTS) based
on time-resolved fluorescence lifetime (FLT) detection, seeking breakthroughs in the early phase of drug
discovery with unprecedented quality, speed, and precision. UA brings expertise in MyBP-C and cardiac
muscle biophysics, biochemistry, and physiology. In a new publication, this collaborative team has identified
the first compounds that bind to MyBP-C and modulate its interaction with actin. The goal of this project is to
demonstrate proof-of-concept that drug targeting of MyBP-C is a powerful platform for discovery of novel
therapies to affect cardiac muscle protein function and ultimately patient outcomes in heart failure. Aim 1
studies will use a primary HTS assay of a 50,000-compound library of diverse and drug-like small molecules
(now justified by recently completed screens on a small validation library), using a novel FRET assay, to find
compounds that affect the interaction of MyBP-C-with actin. The fluorescence lifetime FRET (FLT-FRET)
assay uses site-specific fluorescent probes attached to actin and MyBP-C domains C0-C2. FLT measurements
provide a precise readout of protein binding and conformation. Small-molecule Hits will be evaluated to select
compounds with highest affinity interactions and/or sensitivity to phosphorylation. Aim 2 studies will use
secondary assays (lower throughput) to determine efficacy of Hit compounds on function. Selected compounds
will be evaluated by biochemical, biophysical, and physiological assays for effects on MyBP-C function, actin
binding, and contractility in cardiac cells. These novel screening strategies address the key missing aspect,
early-phase structure-based drug discovery, to enable MyBP-C therapeutic development, as needed to fine-
tune contractility and improve patient quality of life and survival. In Phase I we will validate the HTS assay for
application to commercial-scale drug screening. In Phase II we will enhance potency and specificity with
medicinal chemistry, evaluating the most promising compounds in increasingly physiological/pathological
conditions for the heart failure indication. Letters from major pharmaceutical co...

## Key facts

- **NIH application ID:** 10483462
- **Project number:** 1R43HL162329-01A1
- **Recipient organization:** PHOTONIC PHARMA, LLC
- **Principal Investigator:** Brett A Colson
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $306,471
- **Award type:** 1
- **Project period:** 2022-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10483462

## Citation

> US National Institutes of Health, RePORTER application 10483462, High-throughput discovery platform for modulators of cardiac muscle proteins to treat heart failure (1R43HL162329-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10483462. Licensed CC0.

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