Pannex’ Panx1 blocker platform
We have developed a platform for design of optimal small molecule Panx1 blocker candidates using a modified version of rational drug design, in silico models, channel docking studies utilizing the 3D structure of human Panx1, ATP release tests and other screening tests.
The selection of initial target cancer indications for discovery and development is based on criteria including scientific data on malignancies characterized by overexpression of Panx1 linked to poor clinical outcome and survival, cancer stage and unmet clinical market need, promising data from animal models using nonspecific Panx1 blockers, supportive in vitro and in vivo data and additional evidence in literature with biopsies, such as gene profiling.
Candidate compounds are investigated for cancer cell viability, cytotoxicity, ATP release and metabolic clearance. Our studies have demonstrated reduction of ATP and cell viability in cancer cells but not in normal cells. Metabolic profile and off target pharmacology studies have shown no interaction with other receptors/channels/enzymes for some of the candidates.
Development summary Panx1 blockers
• 405 rationally designed small molecule Panx1 blockers were designed, and 40 were synthesized.
• Design was based on the human Panx1 3D structure, our pioneering molecule PX001 and known nonspecific Panx1 blockers.
• 7 different compound classes with different physicochemical properties were employed to spread possible structural risks and allow adaption for specific cancer types.
• In silico screening was utilized for developability, toxicophoric groups and metabolic liabilities.
• All compounds were designed for easy synthesis and accessible structural fine tuning.
• In addition to cancer indications, several candidates have demonstrated promising results in animal models of chronic pain and opioid withdrawal.
Broad IP coverage
• Comprehensive composition of matter and use provisional patent filed in August 2022 (USPTO)
• Broad protection:
– Compounds within a broad chemical spectrum
– 7 compound families, giving flexibility for further lead optimizations
– Therapeutic use in a broad spectrum of diseases (cancer, CNS, cardiovascular)
Competitive advantages of Panx1 blockers
Panx1 blockers are in development as cancer therapeutics. Significant efficacy and safety advantages may include, among others:
• Increased efficacy: upstream mechanism of action blocks multiple downstream pathways
• Increased safety: massive Panx1 overexpression in tumor cells; cells must be in activation mode to respond to Panx1 blockers