Background

The SK-Channels project focuses on developing a selective small molecule positive allosteric modulator (PAM) targeting the KCa2.2 (SK2) ion channel. This approach aims to treat spinocerebellar ataxia type 2 (SCA2) and essential tremor (ET), conditions linked to Purkinje cell dysfunction in the cerebellum. Building upon prior research demonstrating that modulation of SK channels can normalize Purkinje cell firing patterns and improve motor function in SCA2 mouse models, the project seeks to advance lead compounds with high selectivity and favorable pharmacokinetic properties.

Commercial Potential

The market for neurodegenerative diseases like SCA2 and ET is substantial, with SCA2 symptomatic care estimated at $400 million annually and ET affecting approximately 2.2% of the U.S. population. The development of a selective KCa2.2 modulator offers a differentiated therapeutic approach compared to existing treatments, such as Troriluzole, by potentially providing improved efficacy and reduced side effects. The project's focus on rare diseases like SCA2 also presents opportunities for orphan drug designation and expedited regulatory pathways.

Milestones

Milestone 0: Replication Study

Validate the selectivity and efficacy of lead compounds 5a and 2q. Test 16 original compounds and 30 additional analogs for selectivity on KCa2.2 over KCa2.3 channels.

Required Funding: Approximately $58,000

Duration: Unspecified

Milestone 1: Lead Optimization

Identify and optimize lead compounds with improved selectivity and drug-like properties. Utilize computational chemistry and SAR data to design and synthesize over 100 new analogs; perform in vitro ADME profiling.

Required Funding: $472,000

Duration: Unspecified

Milestone 2: Preclinical Candidate Selection

Advance the most promising compound(s) to in vivo pharmacokinetic studies. Conduct DMPK studies in rodent and dog models to assess bioavailability, half-life, BBB penetration, and off-target activity.

Required Funding: Unspecified

Duration: Unspecified

Senior Review

The project has received positive evaluations from senior reviewers, highlighting the solid scientific foundation and the unmet medical need in treating SCA2 and ET. The selective targeting of KCa2.2 channels is considered a promising approach, with the potential for disease-modifying effects. While acknowledging the challenges associated with ion channel drug development and the need for further validation, reviewers support the project's progression through its defined milestones.