Research at ³ÉÈË´óƬSmall molecule antagonists against drp1 offer new treatment opportunity for PAH and other diseases with increased mitochondrial fission
Background
Pulmonary Arterial Hypertension (PAH) is a heterogeneous group of diseases characterized by a progressive increase in pulmonary arterial resistance (PVR), which causes a significant burden in terms of quality of life, right heart failure and premature death. Clinically, main signature of PAH is the remodeling of the small pulmonary vessels. There are currently 14 PAH-indicated drugs, but they don’t target the adverse vascular remodeling that obliterates, obstructs, and stiffens the pulmonary vasculature, and most do not improve the function of the right ventricle. Thus, there remains an urgent need for disease modifying agents to improve mortality outcomes in PAH.
Research studies have confirmed that a key pathological change in PAH is abnormal mitochondrial dynamics, which includes mitochondrial fission, fusion, and autophagy. The GTPase dynamin-related protein 1 (drp1) is a key protein in mitochondrial fission and Drp1 is over-expressed and over-activated in PAH. Furthermore, other studies show that a proliferative, apoptosis-resistant, cancer-like phenotype occurs in PASMCs, endothelial cells, and fibroblasts in established PAH. Drp1 plays a key role in this proliferation indicating that drp1 inhibition could have diseases modifying effects.
Technology Overview
We have identified new antagonists of Drp1. Over 3200 virtual compounds were screened against crystal structure of drp1 to identify candidates that would bind the GTPase domain of Drp1. 17 compounds were then tested for biological activity with two having high activity at inhibiting GTPase activity. Two (drpitor1 and drpitor 1A) compounds demonstrated inhibitory activity > 175-fold (EC50 ~50 nM) than the gold-standard research tool compound Mdivi-1 at reducing cellular mitochondrial fission.
There are currently no mitochondrial-directed drugs for treating PAH. All cell types in the pulmonary vasculature in PAH, including pulmonary arterial smooth muscle cells (PASMC), endothelial cells, and fibroblasts, have increased expression and drp1 activity which produces acquired abnormalities of mitochondrial metabolism including increased fission (and depressed fusion), which favor cell proliferation and inhibit apoptosis. Thus, inhibition of drp1 represents a potential treatment to reverse PAH or significantly add benefit in combination with existing therapies.
Benefits
Drpitor1a inhibits recombinant Drp1’s GTPase while inhibiting fission in human PAH PASMC without preventing Drp1’s translocation to mitochondria. In vitro Drpitor1a slows human PAH PASMC proliferation and increases mitochondrial apoptosis, while in vivo Drpitor1a regresses monocrotaline (MCT)-induced PAH. Reassuringly, Drpitor1a has minimal effects on fission or cell proliferation in normal cells. Drpitor1a has few off target effects and does not significantly alter respiration, electron transport chain (ETC) activity, or the expression of fusion mediators in human PAH PASMC. Likewise, Drpitor1a therapy elicits no effects on the systemic circulation in normal rats and causes no toxicity in MCT-PAH rats or normal rats. We observed a sexual dimorphism, such that Drpitor1a is more effective in female MCT-PAH rats. Thus, Drp1 is a promising therapeutic target in PAH and Drpitor1a a potential therapeutic molecule.
Animals tested: n=8 for PBS+NS, n=6 for PBS+Drpitor1a, n=11 for MCT+NS, and n=9 for MCT+Drpitor1a). A, Drpitor1a _reversed_ pulmonary vascular remodeling as measured by reduced percentage medial thickness of small PAs in MCT-PAH rats. H&E staining. B, Drpitor1a reversed RV hypertrophy as measured by RV cardiomyocyte cross-sectional area in MCT-PAH rats. H&E staining. C, Drpitor1a reversed RV fibrosis as measured by percentage of RV fibrotic area in MCT-PAH rats. Picrosirius staining. Drpitor1a indicates Drp1 inhibitor; MCT, monocrotaline; NS, normal saline; PA, pulmonary artery; PAH, pulmonary arterial hypertension; and RV, right ventricle.
Drpitor1A treatment significantly benefited PAH mice by reducing RVSP, lowering pulmonary vascular resistance, significantly reduced the degree of RV hypertrophy (Fulton Index) and improved hemodynamics (CI).
Chart summarizing benefits on clinical measures of PAH in a monocrotaline murine model of PAH. Note the lack of negative effects of Drpitor1A in normal control mice on these same variables supporting the safety of drp1 inhibition in vivo. The safety of drp1 inhibition in vivo is also supported by no difference between treated/untreated normal and PAH mice examining hematological variables (Hb, RBC, platelets), hepatotoxicity variables (ALT, AST, bilirubin, albumin) and renal toxicity (BUN, creatinine, and phosphorus),
Applications
Overexpressed drp1 and concurrent increased mitochondrial fission is seen in many diseases besides PAH including other cardiovascular diseases (heart failure, ischemia-reperfusion injury), cancers, and neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s disease.
Opportunity
³ÉÈË´óƬ are open to considering a number of mechanisms of commercializing inhibitors of drp1.
Patents
- US Patent 11,229,629, Inhibitors of Mitochondrial Fission
- Pending Canadian Patent Serial No. 3,077,286 Inhibitors of Mitochondrial Fission
IP Status
Patented
Seeking
- Development partner
- Commercial partner
- Licensing
- Seeking investment
Posted
September 3, 2024