The team at Arkuda Therapeutics, a leading US-based biotechnology company, joined forces with BioAscent to discover novel small molecules targeting neurodegenerative diseases. The collaboration has resulted in the publication of a paper titled 'Discovery and Characterization of Novel TRPML1 Agonists'.

Arkuda’s decision to partner with BioAscent was driven by BioAscent’s extensive expertise in assay development and high throughput screening (HTS), supported by a highly skilled in silico discovery team. The project's focal point was the development of a robust cell-based assay to assess TRPML1-mediated calcium release followed by an HTS campaign of BioAscent's 125K library of diverse lead-like compounds and then optimisation of the validated hits guided by in silico design.

Dr Jim Lanter, Vice President of Medicinal Chemistry at Arkuda, commented: “We selected the BioAscent team as our CRO partner for this project due to their demonstratable capabilities in high throughput screening for this target class, combined with their expertise in structure-based computational chemistry to rapidly prioritise hits.  This successful collaboration opens new avenues for targeting lysosomal functions implicated in a spectrum of autoimmune conditions and neurodegenerative disorders.”

BioAscent's team designed and developed a robust, reproducible, and scalable calcium flux FLIPR assay, tailored to measure small molecule activation of TRPML1. A rigorous assay development programme optimised factors such as signal-to-background ratio, Z’ value, DMSO tolerance, and intra- and inter-plate variability, followed by an assessment of the assay sensitivity to BioAscent’s PAINS library, a collection of compounds known to exhibit various interference/PAINS mechanisms.

Dr Stuart McElroy, Director of Biosciences, commented: “It was a very rewarding experience for us to play an integral role in the collaborative project team with Arkuda. Our extensive assay development and screening experience meant we identified and solved issues with the assay that could have made it quite difficult to rapidly validate the hits, which led to a very positive screen outcome.”

The screening cascade involved a primary screen of BioAscent's 125K library, followed by hit confirmation, potency determination, and de-selection screening. Leveraging advanced 3D similarity and in silico docking techniques implemented by BioAscent's Dr Angelo Pugliese, further Structure-Activity Relationship analysis of the hit molecule led to the synthesis of a selective lead compound.

Dr Angelo Pugliese, Associate Director of In Silico Discovery, commented: “It has been a pleasure to collaborate with the Arkuda team. Project meetings were always something we were looking forward to and that says everything about the nature of the interaction. Our computational chemists’ structure-based drug design experience was instrumental to design and prioritise conformationally locked macrocyclic analogues with improved potency while retaining the selectivity”.

This discovery opens new avenues for targeting lysosomal functions implicated in a spectrum of autoimmune conditions and neurodegenerative disorders. With this collaborative work, Arkuda Therapeutics reinforces their commitment to pioneering innovative solutions in the fight against neurological diseases.

The full study is published in Bioorganic & Medicinal Chemistry Letter, and available for download here.