1. Project profile

Target : A GTPase associated with fibrosis (upstream of MRTF-A)

Indications: Chronic HFrEF and HFpEF

Research phase: IND approval

Cooperation demands: license out

2. Human genetics evidence linking the novel target with heart failure

(1) We reanalyzed public single-cell RNAseq datasets of human left ventricular samples (GSE218392) to investigate the role of the GTPase in heart failure (HF) and externally validated our findings.

(2) Aberrantly high expressions of the GTPase were observed in fibroblasts and cardiomyocytes from heart tissues of heart failure patients, indicating an association with pathological fibrosis and cardiac dysfunction.

(3) Aberrant activation of the GTPase signaling was observed in fibroblasts and cardiomyocytes from the heart tissues of heart failure patients, suggesting its potential as a novel therapeutic target to mitigate disease progression.

3. Novel inhibitor design strategy

(1) The GTPase acts as a Molecular Switch that cycles between an inactive GDP-bound and an active GTP-bound conformation;

(2) TP1001 doesn’t act directly on the GTPase in its active form. Instead, it works by keeping the GTPase in its inactive state. This way, it can effectively stop the active GTPase from becoming too active, and in turn, preve the harmful pathological reactions that active GTPase causes.(3) The GTPase activation increases the nuclear translocation of MRTF-A, promoting the expression of fibrosis and hypertrophy-associated genes.TP1001 disrupts the nuclear translocation of MRTF-A by inhibiting the GTPase activation, which decreases the expression of fibrosis markers like collagen and fibronectin in cardiac fibroblast and hypertrophy markers like MYH7 in cardiomyocytes to improve cardiac remodeling.

4. Results and data

TP1001 significantly improves myocardial remodeling in animal models of ischemic heart failure (LAD ligation in rats)
TP1001 significantly decreased the level of biomarkers including CK, LDH，NT-proBNP and Ang II in plasma;

TP1001 obviously reduced collagen deposition and fibrosis;

In vivo studies on HFpEF mouse models demonstrated that TP1001 ameliorated cardiac diastolic dysfunction and reduced diastolic ventricular wall thickness
TP1001 at low, medium, and high doses significantly improved E/e′ , E/A , IVRT and IVCT in HFpEF mice;

The toxicological studies under GLP showed TP1001 has an excellent safety profile , no significant changes in ECG and blood pressure and excellent safety margin;

a Data from a rat PK study administrated a single dose of 2 mg/kg.

Note: All the calculation were based on a human bodyweight of 60kg