Creating a sustainable pipeline of epitranscriptomics drug targets

 
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Gotham is committed to building a pipeline based on the promise of the epitranscriptomics approach.

We will focus initially on targets with the most compelling links to disease and move on rapidly to develop small molecule inhibitors employing diverse screening strategies coupled with state-of-the art medicinal chemistry.

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360°

At Gotham, we apply a 360-degree approach to the entire process of drug discovery. In target selection, we will consider and investigate the full therapeutic potential of a given target’s biology even if first solid evidence points towards a specific subindication.

When linking distinct targets to the presumably most productive areas of the chemical space, we will nonetheless interrogate different spatial areas of the infinite chemical universe, thus increasing the likelihood to embark into iterative optimization campaigns with best possible chemical matter.

Our screening approach is customized for each target increasing the likelihood of success. We combine traditional high-throughput screening with fragment-based lead generation and DNA-encoded library screenings to increase hit rates and hit quality as starting with high quality hits will significantly reduce drug discovery timelines.

Identifying the highest quality hit matter requires thorough triaging incorporating a combination of data sets such as the quantification of binding strength, detailed enzymology that accounts for thermodynamics and kinetics, structural biology data when in solution as well as from crystal structures, and the stringent evaluation of chemical attractiveness avoiding nuisance compounds.

Our iterative optimization campaigns are performed using multi-dimensional optimization goals not only improving affinity, but also cell-based efficacy, selectivity within the target family and broad target panels, solubility, permeability, stability, bioavailability, the PK profile required for certain routes of administration, target engagement in cell culture and in in vivo settings and in vivo safety and efficacy.

 
 

Since its foundation in 2017, Gotham has continuously worked on confirming key epitranscriptomics findings in the literature using shRNAs, siRNAs and CRISPR technology.

We continue to evaluate the documented mRNA modifications and discoveries from our labs, and the role that these play in human diseases.

We then transition to the use of small molecule tool compounds and cell-based assays to provide insights into the mechanism of action and develop pharmacodynamic biomarkers and PK/PD models, leading to optimized lead candidate generation with our CRO partners.

 
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