PX578 POLG activator program
phase 1drug program · high · Thu Jan 01 2026 00:00:00 GMT+0000 (Coordinated Universal Time)
Increase mitochondrial DNA and restore or modulate cellular energetics for POLG-related mitochondrial diseases, mitochondrial DNA depletion syndromes, and potentially broader degenerative diseases.
First-in-class small-molecule POLG activator targeting mitochondrial DNA polymerase activity to increase mtDNA synthesis.
Lead therapeutic in Phase 1 clinical development in the United States.
Related small-molecule activator work restored function to mutant POLG variants in vitro and activated mtDNA synthesis in pediatric patient cells, enhancing oxidative phosphorylation biogenesis and cellular respiration.
SAMHD1 mitochondrial DNA depletion program
preclinicaldrug program · medium · Thu Jan 01 2026 00:00:00 GMT+0000 (Coordinated Universal Time)
Restore nucleotide balance and rescue mitochondrial function in mitochondrial DNA depletion models.
Therapeutic targeting of SAMHD1 in in vitro and in vivo mtDNA depletion models.
Listed in Pretzel pipeline and described in a 2026 publication/presentation title.
Reported rescue of mitochondrial function in in vitro and in vivo mtDNA depletion models.
PX578 POLG program
phase 1drug program · high · Wed Apr 09 2025 00:00:00 GMT+0000 (Coordinated Universal Time)
Develop a therapeutic for POLG-related mitochondrial diseases and other conditions related to mtDNA depletion by restoring mutant mitochondrial DNA polymerase activity and supporting mitochondrial bioenergetics.
Small molecule activators targeting mutant mitochondrial DNA polymerase activity within Pretzel's bioenergetics restoration franchise.
PX578 recently entered Phase 1 clinical development in the United States.
A 2025 Nature publication reported that small molecules restore mutant mitochondrial DNA polymerase activity.
PZL-A POLG activator research program
preclinicalresearch program · high · Wed Apr 09 2025 00:00:00 GMT+0000 (Coordinated Universal Time)
Restore mutant mitochondrial DNA polymerase gamma activity and treat POLG disorders or other severe conditions linked to mitochondrial DNA depletion.
Small-molecule allosteric activator binding at the interface between POLG catalytic and accessory subunits to restore mtDNA synthesis.
Published discovery and characterization of PZL-A in Nature in 2025.
PZL-A restored wild-type-like activity to mutant POLG forms in vitro and activated mtDNA synthesis in cells from pediatric patients with lethal POLG disease.
POLRMT antisense metabolic program
preclinicaldrug program · high · Wed Jan 01 2025 00:00:00 GMT+0000 (Coordinated Universal Time)
Modulate mitochondrial DNA transcription to address metabolic disease phenotypes including obesity, hepatosteatosis, and energy expenditure.
Antisense oligonucleotide targeting POLRMT to inhibit mammalian mtDNA transcription.
2025 Obesity Week presentation titled "Antisense Oligonucleotide Targeting POLRMT Reduces Weight and Increases Energy Expenditure in Mice."
Supplied publication records report that POLRMT-targeting ASO reduced weight and increased energy expenditure in mice; related 2024 Nature Metabolism paper reports inhibition of mammalian mtDNA transcription reversed diet-induced hepatosteatosis and obesity.
POLRMT obesity and metabolic program
preclinicaldrug program · medium · Mon Jan 01 2024 00:00:00 GMT+0000 (Coordinated Universal Time)
Modulate mitochondrial DNA transcription to address obesity and metabolic disease, including diet-induced hepatosteatosis and obesity.
Inhibition of mammalian mitochondrial DNA transcription, linked to POLRMT biology and Pretzel's mitochondrial bioenergetics platform.
A 2024 Nature Metabolism publication reported reversal of diet-induced hepatosteatosis and obesity through inhibition of mammalian mtDNA transcription.
Published results indicate that inhibition of mammalian mtDNA transcription can paradoxically reverse diet-induced hepatosteatosis and obesity.
Mitochondrial bioenergetics and mtDNA modulation platform
exploratoryplatform · high · Mon Sep 12 2022 00:00:00 GMT+0000 (Coordinated Universal Time)
Harness mitochondrial biology to develop therapies for diseases associated with bioenergetic dysregulation by controlling replication and transcription of mitochondrial DNA.
Platform approach focused on modulating mitochondrial DNA replication and transcription to affect mitochondrial bioenergetics.
Pretzel launched with $72.5 million Series A financing to pioneer mitochondrial therapies.
The platform underlies listed programs targeting POLG, SAMHD1, POLRMT, and undisclosed indications.
Mitochondrial biology and cellular energetics platform
exploratoryplatform · high · Mon Sep 12 2022 00:00:00 GMT+0000 (Coordinated Universal Time)
Discover and develop medicines that modulate mitochondrial function, mitochondrial DNA replication, mitochondrial DNA transcription, and cellular energetics across rare, neurodegenerative, metabolic, and other diseases.
Platform focused on novel mitochondrial targets, including control of mitochondrial DNA replication and transcription to restore or modulate cellular energetics.
Platform supports a listed pipeline including POLG/PX578, SAMHD1, POLRMT, and undisclosed programs.
POLRMT inhibitor oncology research program
exploratoryresearch program · low · Tue Sep 07 2021 00:00:00 GMT+0000 (Coordinated Universal Time)
Explore POLRMT inhibition using coumarin derivatives for cancer treatment, potentially in combination with standard cancer therapies.
Coumarin derivative POLRMT inhibitors described in patent records for treatment of cancer.
Patent family records WO2019057821A1 and US20200291011A1 describe coumarin derivatives and uses for treatment of cancer; US application granted as US11111238B2 according to supplied record excerpt.
POLRMT antisense metabolic disease program
preclinicaldrug program · high
Reduce weight, increase energy expenditure, and reverse diet-induced hepatosteatosis and obesity through modulation of mitochondrial DNA transcription.
Antisense oligonucleotide targeting POLRMT; related research inhibits mammalian mtDNA transcription.
2025 Obesity Week presentation on POLRMT antisense oligonucleotide effects in mice.
In mice, antisense targeting of POLRMT reduced weight and increased energy expenditure; related mtDNA transcription inhibition was reported to reverse diet-induced hepatosteatosis and obesity.
SAMHD1 program
undiscloseddrug program · medium
Develop a program targeting SAMHD1 for rare, neurodegenerative, metabolic, or other diseases associated with mitochondrial bioenergetic dysregulation.
Pretzel lists SAMHD1 among pipeline targets within its mitochondrial bioenergetics and mtDNA modulation approach.
Listed in Pretzel's pipeline.
Undisclosed mitochondrial target program
undiscloseddrug program · low
Develop a mitochondrial biology therapeutic program against an undisclosed target.
Undisclosed intervention within Pretzel's mitochondrial biology and cellular energetics pipeline.
Listed in the company pipeline as "Undisclosed."
Undisclosed pipeline program
undiscloseddrug program · low
Develop additional therapies within Pretzel's mitochondrial bioenergetics and mtDNA modulation pipeline.
Undisclosed program listed in Pretzel's pipeline.
Listed as an undisclosed pipeline program.
