23 May 2019 - - US-based biotechnology company Gotham Therapeutics, which is developing a novel drug class targeting RNA-modifying proteins, and Dutch contract research organisation ZoBio have made significant progress made as part of their collaboration to identify therapeutic lead candidates for Gotham's initial portfolio of epitranscriptomic targets, the companies said.

In the first project pursued within the collaboration, the initial phase for Gotham's drug discovery project targeting the METTL3/METTL14 complex has been completed and a portfolio of small-molecule candidates will be further evaluated.

In January 2018, Gotham and ZoBio initiated a collaboration to develop small-molecule inhibitors of the "writer" protein complex METTL3/METTL14, a SAM-dependent methyltransferase that modifies mRNA encoded adenosine in the messenger RNA to m6A and thereby regulates protein expression.

The collaboration aims to use ZoBio's unique capabilities in biophysics-based drug discovery and structural biology to attack this novel target.

Through extensive protein engineering, multiple forms of the complex have been generated that enable all of the planned studies.

Using Surface Plasmon Resonance to screen ZoBio's diverse fragment library, the collaboration has resulted in the discovery and validation of multiple, drug-like substances that selectively modulate the function of the METTL3/METTL14 complex and have the potential to be optimized towards pre-clinical candidates.

ZoBio's unique expertise in both Nuclear Magnetic Resonance spectroscopy and protein crystallography has enabled the deep understanding of the mode of action of these chemotypes at atomic resolution.

With their combined arsenal of capabilities and expertise, Gotham and ZoBio are well positioned to generate in vitro and in vivo active inhibitors that will further Gotham's programs and the field of epitranscriptomics.

Gotham Therapeutics has assembled a team and network to establish a novel drug class targeting RNA-modifying proteins.

By changing the activity of proteins that modify messenger RNA, we aim to develop new treatment options for patients suffering from cancers, auto-immune and neurodegenerative diseases.

It is applying a 360-degree approach to small molecule drug design to build a pipeline based on the promise of this rapidly emerging biopharmaceutical field.

ZoBio offers proprietary, orthogonal technology and more than 15 years of experience to enable its integrated fragment-based drug discovery engine for a range of pharmaceutical targets.

The engine is based on a platform of high throughput protein engineering, highly diverse fragment libraries, proprietary biophysical screening technologies and complementary structural biology approaches designed to provide data in the broadest possible target space.

The company synthesises this information to generate actionable medicinal chemistry hypotheses to bridge the divide between fragment and lead.