Ischemic heart disease (IHD) — caused by reduced blood flow to the heart — is the leading cause of premature death worldwide and represents a major public health challenge. Despite significant advances in treatment and management, mortality and morbidity remain unacceptably high, placing enormous burden on patients, families and health systems.
This huge unmet medical need urgently requires novel strategies to improve survival, reduce disability and enhance quality of life. Our project is developing breakthrough therapeutic agents targeting a key inflammatory pathway — p38 MAPK — that drives damage in acute heart attacks and the progression to heart failure.
Why inflammation matters in heart disease
When a heart attack occurs, the immediate damage from oxygen deprivation is just the beginning. Inflammation triggered by tissue injury continues to damage the heart muscle in the days and weeks following the event, contributing to scar formation, heart muscle weakening and eventual progression to heart failure.
The p38 MAPK signalling pathway plays a pivotal role in this inflammatory response. By blocking this pathway, we can potentially reduce ongoing heart damage, preserve heart function and prevent or delay progression to heart failure.
Learning from past failures
Previous attempts to develop p38 MAPK inhibitors have failed, primarily due to severe liver toxicity that emerged during clinical trials. These failures highlighted a critical challenge: creating inhibitors selective enough to block harmful inflammation whilst avoiding off-target effects that damage the liver.
Our approach addresses this challenge head-on through computer-assisted drug design and careful structure-activity relationship studies.
VCP979: a promising lead compound
Using rational drug design, we've developed VCP979 — a novel p38 MAPK inhibitor with properties that distinguish it from failed predecessors:
Safety profile
- No abnormal liver function in preclinical testing (the major cause of previous program failures).
- Chemical structure avoids known genetic toxiphores (DNA-damaging components).
- No problematic interactions with CYP450 enzymes (which metabolise most drugs).
- Minimal off-target effects.
Efficacy
- Selective inhibition of p38 MAPK pathway.
- Demonstrated effectiveness in cell-based studies.
- Proven efficacy in animal models of heart disease.
- Low toxicity across multiple test systems.
VCP979 possesses genuine drug-like properties, meaning it has the characteristics necessary to become a viable medication: appropriate absorption, distribution, metabolism and safety profile.
Next steps: optimisation and validation
Our current work focuses on optimising VCP979 to create the best possible clinical candidate:
Pharmacokinetic optimisation
- Improving how the drug is absorbed, distributed and eliminated.
- Ensuring therapeutic concentrations reach the heart.
- Extending duration of action to enable convenient dosing.
ADMET profiling
- Absorption: how well the drug enters the bloodstream.
- Distribution: how effectively it reaches target tissues.
- Metabolism: how the body processes the drug.
- Excretion: how the drug is eliminated.
- Toxicity: comprehensive safety assessment across organ systems.
Validation studies
- Testing in multiple in vitro disease models.
- Evaluation in in vivo models of heart attack and heart failure.
- Comparison with existing therapies to demonstrate superiority.
- Dose-finding studies to establish optimal therapeutic levels.
Toward clinical trials
We expect to identify final drug candidate(s) suitable for clinical development, complete investigational new drug (IND) profiling required by regulatory authorities, and ready the compound for Phase I clinical trials in humans.
If successful, this research could provide the first effective anti-inflammatory therapy specifically designed to prevent heart failure following heart attack — addressing an enormous unmet need and potentially saving thousands of lives annually.
Why this research matters
Current heart attack treatments focus on restoring blood flow (opening blocked arteries) and managing symptoms. We have no approved drugs that specifically target the inflammatory damage driving progression to heart failure. VCP979 could fill this critical gap, offering:
- Reduced heart muscle damage following a heart attack.
- Prevention or delay of heart failure development.
- Improved survival and quality of life for heart attack survivors.
- Reduced healthcare costs from heart failure hospitalisations.
For the millions of people who survive heart attacks each year, preventing the devastating progression to heart failure represents one of the most important therapeutic opportunities in cardiovascular medicine.