DHP’s portfolio of 25 unique molecules are being developed with unique MOAs to provide a specific combination of targeted effects on key biological receptors and physiological/biochemical pathways in the body that, to the best of our knowledge, has not been achieved by current drugs on the market today.

As part of the discovery and development of the active molecule in DHP’s lead product candidate, DHP-101, our scientists identified three biological targets that play a key role in modulating the effects of several diseases, including multiple sclerosis and systemic sclerosis. These targets are the cannabinoid receptor type 2 (CB₂), the peroxisome proliferator-activated receptor gamma (PPARγ), and the hypoxia-inducible factor (HIF)-1.

Cannabinoid Receptor Type-2 (CB₂)
As part of the body’s endocannabinoid system, a receptor system that functions to maintain homeostasis (balance) in the body via interaction with endocannabinoids produced in the body, CB₂ plays a key role in modulating neuroprotection, inflammation, immunomodulation, and vascular responses, without introducing psychotropic effects. In studies conducted to date, our lead molecule has shown enhanced CB₂ receptor modulation activity that could potentially provide therapeutic benefits.

Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)
The PPARγ nuclear receptor is implicated in regulating cell growth, lipid metabolism and blood sugar. It is broadly expressed and has been shown to prevent inflammation, dermal fibrosis and loss of fatty tissue. In studies to date, our lead molecule has shown the ability to modulate the activity of PPARγ through a “partial activation” MOA, which avoids the potential negative effects demonstrated with full activation, providing the potential for immunomodulatory and neuroprotective activities. For instance, PPARγ modulation promotes oligodendrocyte progenitor cell differentiation and enhances their antioxidant defenses that may affect remyelination.

Hypoxia-Inducible Factor (HIF) Pathway
The HIF pathway is a protein complex that is integral in the body’s response to reduced oxygen concentrations. Cellular adaptation to severe (pathological) or mild hypoxia (hypoxia preconditioning) begins immediately with the activation of the HIF pathway, and regulates genes involved in red blood cell production, angiogenesis, neuroprotection, myelination, vascular tone, immunity, and other biological processes. HIF activation may play a role in the inflammatory and phases of MS, and may be linked to neuroprotection, including protection of the blood brain barrier (BBB), and promotion of myelination. In studies conducted to date, the active pharmaceutical ingredient, VCE-004.8, in our lead product candidate (DHP-101) has shown activation of the HIF pathway, indicating potential for neuroprotection and vascular protection capabilities.

Our scientists have identified three key biological receptors and pathways in the body affected by the active pharmaceutical ingredient in DHP-102 (VCE-003.2) that can potentially impact physiological processes pertinent to these complex diseases. These targets are peroxisome proliferator-activated receptor gamma (PPARγ), extracellular signal-regulated kinases (ERK), and chicken ovalbumin upstream promoter transcription factor-interacting protein (Ctip2).

Peroxisome proliferator-activated receptor gamma (PPARγ)
PPARγ has a wide spectrum of biological functions, regulating mitochondrial function, mitochondrial turnover, energy metabolism, antioxidant defense and redox balance, immune responses and fatty acid oxidation. Ligand activators of PPARγ have been tested successfully for their neuroprotective potential in certain central nervous system diseases such as stroke, Parkinson´s disease, Huntington’s disease and certain types of ataxias.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2)
Accumulating evidence supports a key role for extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling in the embryonic development of the central nervous system and in the regulation of adult brain function. ERK1/2, one of the most well characterized members of the mitogen-activated protein kinase family, regulates a range of processes, from metabolism and motility to cell death and survival. In the nervous system, ERK1/2 regulates synaptic plasticity, brain development and repair as well as memory formation. Also, it has been shown in preclinical models that activation of ERK1/2 both promote basal dopaminergic cell survival, and that ERK 1/2 also protects these cells from oxidative stress. In addition, ERK1/2 signaling in the depression-implicated brain regions was disrupted during the development of depression, which contributes to the long-lasting and transcription-dependent neuroadaptations critical for enduring depression-like behavior and the therapeutic effect of antidepressants.

Chicken ovalbumin upstream promoter transcription factor-interacting protein (Ctip2)
Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntington’s disease. It has been shown that transcription factor Ctip2 (also known as Bcl11b) is central to MSN differentiation, striatal development and the establishment of the cellular architecture of the striatum. In preclinical models Ctip2 deficiency results in structural striatal defects, impaired spatial learning, and working memory deficits. Furthermore, Ctip2 protein levels are reduced in both human and rodent mutant huntingtin (mHTT)-expressing cells before the onset of MSN degeneration, pointing to a role for Ctip2 in Huntington’s disease pathogenesis.