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 to unveil. HotSpot takes a systems-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.

Leading the Way in Allosteric Drug Discovery

Our sophisticated approach to targeting regulatory hotspots offers many advantages over conventional allosteric approaches, which often rely upon target-blind phenotypic screening.

Functional relevance

Out of the many allosteric pockets visible or predicted in a protein, we target only those regulatory hotspots known to play a critical role in enzyme function

Structurally enabled

In contrast to blind, opportunistic screening, we start with a clear understanding of protein structure and 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 Therapeutics’ SpotFinder™ platform is the first technology platform designed to systematically identify regulatory hotspots and enable the design of potent, selective allosteric modulators. HotSpot’s approach is systematic, computational, scalable and efficient, enabling whole target classes to be assessed simultaneously.

We integrate insights from biology, computational sciences, chemistry and biophysics to systematically identify and drug regulatory hotspots.

Predict

Regulatory sites on proteins are often difficult to identify but possess certain common features that can be uncovered through mining of expertly curated structure, sequence and function datasets. SpotFinder™ uses advanced machine learning techniques to discover the underlying fingerprints of regulatory pockets, thereby cracking nature’s code.

Design

HotSpot uses 3D structure insights from the uncovered pockets to design in-house DNA-encoded libraries (DEL) that comprise millions of exquisitely tailored molecules. In 2019, HotSpot acquired Macroceutics, Inc, a leader in DEL chemistry, to leverage HotSpot’s structure-based drug discovery platform across molecules built on DNA.

Screen

A proprietary screening paradigm has been implemented to identify hotspot-targeted molecules with differentiated pharmacology. HotSpot leverages hundreds of bespoke proteins to display the hotspot in the correct conformation; cell-based screening to uncover novel pharmacology e.g. degradation; hotspot-targeted binding assays; and proprietary X-ray structures to accelerate structure-based design.

Using this approach we have both uncovered regulatory hotspots and delivered novel drug candidates across several important protein classes, including kinases, transcription factors and E3 ligases.

Learn more About Our Targets