Phenyl Indole Allosteric Inhibitors of p97 ATPase: Small Molecules for Cancer and Neurodegenerative Disease Treatment

This technology comprises a novel class of phenyl indole compounds that selectively inhibit p97 ATPase, a protein critically involved in cellular protein quality control and implicated in cancer progression and neurodegenerative disease. These allosteric inhibitors offer a promising new therapeutic avenue by targeting p97 with sub-micromolar potency, enabling treatment of cancers and neurodegenerative disorders where current therapies are insufficient.

Description

The technology pertains to a series of chemically defined phenyl indole derivatives that function as allosteric inhibitors of the p97 ATPase enzyme, also known as valosin-containing protein (VCP). p97 plays a critical role in diverse cellular processes including protein quality control, ubiquitin-dependent proteasomal degradation, and endoplasmic reticulum-associated degradation (ERAD). Dysregulation or upregulation of p97 activity is implicated in oncogenic progression and neurodegenerative pathologies. The invention centers on the design, synthesis, and biological evaluation of small molecules that bind allosterically to p97, thereby modulating its ATPase activity. The described chemical entities possess defined substituent patterns on the phenyl indole scaffold, optimized to achieve potent and selective inhibition. Detailed synthetic routes enable the preparation of these compounds, which have been biochemically characterized in vitro to demonstrate their efficacy in attenuating p97 function. The approach leverages structure-activity relationships to enhance potency, selectivity, and drug-like properties, positioning these inhibitors as promising candidates for therapeutic development.

Applications

- Treatment of various cancers characterized by aberrant p97 activity, including those exhibiting elevated protein degradation pathways.
- Therapeutic management of neurodegenerative disorders such as inclusion body myopathy, Paget’s disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis, where p97 dysfunction contributes to pathology.
- Use as molecular probes to elucidate the biological role of p97 in cellular homeostasis and disease mechanisms.
- Potential incorporation into combination therapy regimens, enhancing the efficacy of existing chemotherapeutic agents through synergistic mechanisms targeting proteostasis.
- Platform for the development of further allosteric inhibitors aimed at modulating ATPase activity for diverse biomedical applications.

Advantages

- Selective Allosteric Modulation: By targeting an allosteric site distinct from the active ATP-binding domain, these inhibitors offer high selectivity, potentially reducing off-target effects common with ATP-competitive inhibitors.
- Potent Inhibition of p97 Activity: The compounds exhibit strong biochemical efficacy in vitro, effectively suppressing ATPase function critical to p97’s role in protein degradation pathways.
- Chemical Versatility: The phenyl indole scaffold supports diverse substitutions, enabling systematic optimization of pharmacokinetic and pharmacodynamic properties.
- Therapeutic Relevance: Targeting p97 addresses multiple diseases sharing a common pathogenetic mechanism involving proteostasis dysregulation, expanding the clinical utility of these inhibitors.
- Synthetic Accessibility: Detailed synthetic protocols facilitate scalable compound production, supporting preclinical and clinical development efforts.

Invention Readiness

This technology is at the experimental proof-of-concept stage, with a well-characterized lead series of small molecules identified and synthesized. Biochemical activity has been confirmed across a broad set of analogs using a validated bioluminescent ATPase assay, with select compounds demonstrating nanomolar inhibitory potency. Structure-activity relationships have been thoroughly mapped across key substitution positions, providing a strong foundation for lead optimization. Further studies needed include cellular efficacy and selectivity profiling, pharmacokinetic characterization, in vivo proof-of-concept studies in relevant disease models, and assessment of off-target activity to support progression toward preclinical development.

IP Status

https://patents.google.com/patent/US10633370B2

Related Publication(s)

Banerjee, Soojay, et al. "2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition." Science 351.6275 (2016): 871-875. https://doi.org/10.1126/science.aad7974