A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model

Anorexia nervosa (AN) is a psychiatric illness with the highest mortality. Current treatment options have been limited to psychotherapy and nutritional support, with low efficacy and high relapse rates. Hypothalamic AgRP (agouti-related peptide) neurons that coexpress AGRP and neuropeptide Y (NPY) play a critical role in driving feeding while also modulating other complex behaviors. We have previously reported that genetic ablation of Tet3, which encodes a member of the TET family dioxygenases, specifically in AgRP neurons in mice, activates these neurons and increases the expression of AGRP, NPY, and the vesicular GABA transporter (VGAT), leading to hyperphagia and anxiolytic effects. Bobcat339 is a synthetic small molecule predicted to bind to the catalytic pockets of TET proteins. Here, we report that Bobcat339 is effective in mitigating AN and anxiety/depressive-like behaviors using a well-established mouse model of activity-based anorexia (ABA). We show that treating mice with Bobcat339 decreases TET3 expression in AgRP neurons and activates these neurons leading to increased feeding, decreased compulsive running, and diminished lethality in the ABA model. Mechanistically, Bobcat339 induces TET3 protein degradation while simultaneously stimulating the expression of AGRP, NPY, and VGAT in a TET3-dependent manner both in mouse and human neuronal cells, demonstrating a conserved, previously unsuspected mode of action of Bobcat339. Our findings suggest that Bobcat339 may potentially be a therapeutic for anorexia nervosa and stress-related disorders.

 

Comments：

The study suggests that Bobcat339, a synthetic small molecule that binds to the catalytic pockets of TET proteins, may be effective in treating anorexia nervosa and anxiety/depressive-like behaviors in mice. The researchers found that Bobcat339 decreased TET3 expression in AgRP neurons, leading to the activation of these neurons and increased expression of AGRP, NPY, and VGAT, which resulted in hyperphagia and anxiolytic effects. In a mouse model of activity-based anorexia, treatment with Bobcat339 led to increased feeding, decreased compulsive running, and diminished lethality. The mechanism of action of Bobcat339 involves inducing TET3 protein degradation while simultaneously stimulating the expression of AGRP, NPY, and VGAT in a TET3-dependent manner. These findings suggest that Bobcat339 may potentially be a therapeutic for anorexia nervosa and stress-related disorders. However, further studies are needed to determine the safety and efficacy of this compound in humans.

Related Products

Cat.No.	Product Name	Information
S6682	Bobcat339 hydrochloride	Bobcat339 is a selective cytosine-based TET enzyme inhibitor with IC50 of 33 μM and 73 μM for TET1 and TET2, respectively. Bobcat339 can reduce DNA 5-hydroxymethylcytosine abundance by inhibiting TET enzyme function in living cells and provide support for its utility as a viable pharmacological probe.

Related Targets

DNA Methyltransferase