Research in the Trippier lab involves the application of organic chemistry, medicinal chemistry, bioorganic chemistry and chemical biology to investigate fundamental topics in human disease and develop new strategies to combat devastating conditions.
Natural products continue to provide valuable hit structures in drug discovery, displaying a wide variety of biological activity applicable to the chemical intervention of many human diseases. Despite their often potent activity, naturally occurring molecules were not biologically designed for use in humans and therefore often exhibit many undesirable and potentially harmful side effects such as metabolic instability and toxicity. The power of synthetic medicinal chemistry to identify, synthesize, and modify bioactive molecules has led to the advancement of a multitude of drug candidates into the clinic.
Of particular interest to the group is applying the tools of chemistry to investigate cancer and neurological disorders affecting pediatric patients.
Design, Synthesis, and Evaluation of Mitochondrial Complex II inhibitors for the Treatment of Cancer
Complex II of the mitochondrial electron transport chain represents a novel target in anticancer drug development that makes the identification of innovative small molecule inhibitors of this protein a priority area of research.
Protein mutations are extremely wide ranging, not only across cancers but within tumors and their derived metastases, an effect that contributes to the development of drug resistance. Mitochondria however, are functional, at least to some extent in most cancers and represent a conserved target of action. Complex II inhibition results in a cascade of mechanisms that leads to selective cancer cell death – activation of autophagy, impairment of glutaminolysis, and ROS production making complex II inhibitors an enticing target for future cancer chemotherapeutic discovery.
The group has succeeded in identifying a lead compound that possess potent complex II inhibition activity and has provided proof of concept that inhibition of complex II leads to potent antineoplastic activity.
Design of 17β-hydroxysteriod dehydrogenase / AKR1C3 Inhibitors for the Treatment of Prostate Cancer and Leukemia
The group is designing inhibitors of aldo-keto reductase 1C3 (AKR1C3) an enzyme in the steroidogenesis pathway, and a target of interest in prostate cancer and acute myeloid leukemia (AML), the second most common leukemia in children.
Drug Discovery for Prostate Cancer
Abiraterone Acetate was recently approved by the FDA for the treatment of Castration Resistant Prostate Cancer (CRPC). This drug targets the steroidogenesis pathway preventing the formation of the potent androgens testosterone and 5α-dihydroxytestosterone (DHT), both of which are responsible for driving tumorigenesis. However Abiraterone Acetate causes accumulation of desoxycorticosterone which leads to adverse side effects such as hypertension. Targeting an enzyme downstream in this pathway (AKR1C3) would provide therapeutic effect without the adverse side effects.
The enzyme has several highly homologous isoforms that makes engineering selectivity for AKR1C3 into molecular scaffolds crucial to avoid unwanted side effects. Our efforts center on the optimization of a lead scaffold to improve selectivity, potency and metabolic stability.
Drug Discovery for Acute Myeloid Leukemia
The AKR1C3 isoform is expressed in a range of leukemia cell lines and primary cells to an extent far greater than the C1, C2, and C4 isoforms.
Inhibition of AKR1C3 with the clinically approved drug indomethacin (AKR1C3 IC50 = 1.8 uM) increases sensitivity to the anti-proliferative and pro-differential effects of all-trans-retinoic acid (a clinically approved AML subtype M3 drug. Development of potent and selective AKR1C3 inhibitors is hypothesized to result in pharmaceutical agents that can be employed as adjuvants to enhance the therapeutic effects of cytarabine, the gold standard agent for AML chemotherapy, and possibly other cytotoxic agents for the treatment of a wider range of leukemia’s. The group has shown that a potent AKR1C3 inhibitor can have just this effect.
Drug Discovery and Target Identification for Batten disease
Batten disease or Neuronal Ceroid Lipofuscinoses (NCL) comprise a group of fatal inherited neurodegenerative diseases afflicting children. Progressive deterioration of neurological function results in death by the early twenties. No cure or treatment currently exists beyond managing the symptoms of the disease.
The group, along with our collaborators, are designing and testing small molecule apoptosis inhibitors and chemical probes as potential therapeutics for the treatment of this disease. To date we have succeeded in developing three derivatives that provide enhanced potency over the hit compound and represent excellent leads for further optimization.
PPARδ Agonists for the Treatment of Parkinson’s Disease
Agonism of peroxisome proliferator-activated receptor-δ (PPARδ) has recently been shown to protect against MPTP induced toxicity in in vitro models of Parkinson’s disease (PD). Currently available PPARδ agonists are being developed as potential treatments for metabolic disorders but not PD. This means that the blood-brain barrier (BBB) penetration properties of the compounds are largely unoptimized, obviously to treat PD the PPARδ agonist must get into the brain to engage its target.
The group has identified a completely novel chemical scaffold that shows potent and selective PPARδ agonism which is undergoing optimization to penetrate the BBB.
We are grateful to the following agencies for funding our research:
Current Research Support
NIH / National Cancer Institute
NIH / National Institute for Neurological Disorders and Stroke
NIH / Eunice Kennedy Shriver National Institute of Child Health and Human Development
NIH / National Institute of Ageing
Department of Defense Amyotrophic Lateral Sclerosis Research Program
Nebraska Collaboration Initiative
Child Health Research Institute
Kingdom of Saudi Arabia Cultural Mission to the United States
Past Research Support
NIH / National Center for Advancing Translational Science
Cancer Prevention and Research Institute of Texas
Texas Alzheimer’s Research and Care Consortium
The Rare Genomics Institute
Leukemia Texas
Gilson Program to Accelerate the Sciences
Kingdom of Saudi Arabia Cultural Mission to the United States
Otis Glebe Medical Research Foundation
