Context

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Over the past two decades, scientific research has highlighted the crucial role of excessive chloride ion accumulation in the development of various pathological disorders.

The NKCC1 transporter is a key regulator of intracellular chloride concentration, directly influencing the balance between neuronal excitation and inhibition. Its overactivity leads to increased chloride levels, altering GABAergic polarity: instead of exerting its usual inhibitory effect, GABA becomes excitatory, promoting neuronal hyperexcitability.

So far, Bumetanide, a well-known diuretic, has proven to be an effective NKCC1 inhibitor, reducing intracellular chloride accumulation and restoring GABA’s inhibitory effect. This contributes to better control of neuronal excitability and the regulation of physiopathological processes.

The importance of chloride homeostasis in numerous diseases continues to be confirmed. A recent study analyzing data from 5 million American patients revealed that prolonged use of Bumetanide reduced the risk of developing Alzheimer’s disease (Taubes, Alice, et al., 2022). Among more than 1,000 commonly used molecules, Bumetanide was identified as one of the most promising candidates for treating Alzheimer’s.

Inhibiting NKCC1 is emerging as a promising therapeutic strategy with diverse applications, ranging from the treatment of autism spectrum disorders (ASD) and epilepsy to combating brain tumors and other conditions associated with disrupted chloride homeostasis.

Project

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Aware of the therapeutic potential of NKCC1 inhibition, B&A Oncomedicalis committed to developing new, more specific, and potent molecules.

Supported by Neurochlore and collaborating with world-renowned NKCC1 experts and Edelris, a leader in novel chemical compound development, our goal is to enhance the efficacy of these new compounds while minimizing side effects.

These advances pave the way for innovative treatments with multiple applications, particularly for conditions where chloride homeostasis is disrupted, such as brain tumors and neurodevelopmental disorders.

Results and perspectives

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This partnership has led to the creation of 120 proprietary NKCC1 inhibitors, all protected by patents.

These compounds were first tested on human cell lines to evaluate their ability to inhibit NKCC1. The majority demonstrated an efficacy ranging from 75% to 100% compared to the reference molecule, Bumetanide. Remarkably, two of them even surpassed this benchmark, reaching 120% efficacy. To date, no other NKCC1 inhibitor on the market has shown such promising results.

The discovery of these novel NKCC1 inhibitors marks a major breakthrough, potentially paving the way for a therapeutic revolution by targeting fundamental mechanisms involved in numerous neurological and oncological diseases.