Abstracts

Bexicaserin Exhibits High Selectivity and Specificity for the 5-HT2C Receptor with Low Potential for Off-target Activity

Abstract number : 1.506
Submission category : 7. Anti-seizure Medications / 7E. Other
Year : 2024
Submission ID : 1472
Source : www.aesnet.org
Presentation date : 12/7/2024 12:00:00 AM
Published date :

Authors :
Presenting Author: Morgan Weberg, BS – Longboard Pharmaceuticals, Inc.

Kenneth Mackay, PhD – Longboard Pharmaceuticals, Inc.
Anne Danks, PhD – Longboard Pharmaceuticals, Inc.

Rationale: Bexicaserin is a new molecule that is an agonist at the 5-hydroxytryptamine 2C (5-HT2C) receptor currently in development for the treatment of seizures in patients with developmental and epileptic encephalopathies (DEEs). Many patients with DEEs experience seizures that are highly refractory to current anti-seizure medications (ASMs) and therefore polypharmacy is common in this population. As it is anticipated that bexicaserin will be used in conjunction with other ASMs, we undertook a comprehensive evaluation of bexicaserin’s receptor binding affinity to other clinically relevant molecular targets to help to anticipate any potential off-target effects.

Methods:

The potential of bexicaserin (10 µM) for off-target pharmacological interactions was evaluated using competition radioligand binding assays in a panel containing 176 recombinant human molecular targets, including GPCR’s, transporters, ion channels, nuclear receptors, cytokines, and enzymes transfected into mammalian cells. Follow-up assays to determine the binding affinity (Ki) of any target activities as well as studies to determine functional agonism or antagonism were conducted.

Additionally, bexicaserin was assessed for agonist or antagonist activity in a dedicated panel of 44 CNS targets commonly associated with human abuse potential (G-protein coupled receptors, transporters, ion channels, and nuclear receptors).

Bexicaserin was further investigated for functional kinase inhibition potential using LANCE technology to measure substrate phosphorylation against a screening panel of 45 kinases representing diverse families within the human kinome that are associated with human safety concerns.

Results: Apart from 5-HT2C, bexicaserin did not exhibit significant activity at any of the other targets evaluated, defined by ≥ 50 % inhibition of target binding or kinase inhibition at 10 µM. In separate binding assays, bexicaserin inhibited ligand binding to the human 5-HT2C receptor by 88% and 99.8%. Further studies demonstrated that bexicaserin acts as an agonist of the 5-HT2C receptor, with a binding affinity (Ki) of 44 nM at the 5-HT2C receptor. Additionally, bexicaserin showed > 227-fold selectivity over the 5-HT2A and 5-HT2B receptors.

Conclusions: These data demonstrate that bexicaserin is a specific and selective agonist of the 5-HT2C receptor subtype that is not expected to interact with other molecular targets at clinically relevant doses. As such, bexicaserin’s specificity for 5-HT2C receptors may offer advantages when used in combination with other ASMs by reducing potential adverse effects and drug-drug interactions noted with other approved ASMs due to their off-target engagement. These data convey a greater understanding of bexicaserin’s underlying mechanism while imparting confidence in how it may fit into a complex polypharmacy treatment paradigm.

Funding:

Longboard Pharmaceuticals, Inc sponsored this study.



Anti-seizure Medications