Unexplored biological space
Uncovering regulatory hotspots is a daunting challenge due to the breadth and variety of mechanisms that nature has developed to control the cell. Unlike active sites, regulatory hotspots are hidden from sight and require a deep understanding of protein structure-function. HotSpot takes a system-wide view across all proteins to uncover previously unknown regulatory relationships.
Novel chemotypes
Existing chemical collections have been designed to target active sites and are poorly aligned with the unique properties of regulatory hotspots. HotSpot has designed proprietary screening libraries enriched for pharmacophores that interact with hotspot motifs.
Elegant allostery
Targeting regulatory hotspots offers many advantages over conventional allosteric approaches, that often rely upon target blind phenotypic screening.
Functional relevance
Out of the many pockets visible or predicted in a protein, we know that regulatory hotspots play a critical role in enzyme function
Structurally enabled
In contrast to blind, opportunistic screening, we start with a clear understanding of the structure function
Chemically tractable
The pharmacological footprint of the natural regulatory ligand gives our chemists a valuable starting point for small molecule design
Our process
HotSpot applies a multidisciplinary approach integrating biology, computational sciences, chemistry and biophysics to systematically identify and drug regulatory hotspots.
Uncover
HotSpot’s proprietary SpotFinder™ platform leverages structural, druggability and functional insights to uncover proteins and pathways with regulatory hotspots.
Validate
Tailored chemical probes and engineered protein constructs are used to confirm experimentally a hotspot’s role in protein function.
Screen
Proprietary chemical libraries are screened using state-of-the-art computational and biophysics approaches to yield chemical matter that modulates the hotspot.
Optimize
Structure-based methods serve to optimize early chemical leads toward potent clinical candidates. Selectivity models and conformationally locked x-ray structures are of particular value.
