Elucidating natural hotspot targets

Uncovering natural hotspots is a daunting challenge due to the variety of mechanisms that nature has developed to control the cell. Unlike active sites, natural hotspots are often hidden from sight and require a deep understanding of structure-function to unveil. The Smart Allostery™ platform takes a systems-wide view to uncover protein pockets with previously unknown regulatory relationships.

Approximately 1,500 proteins have been identified containing natural hotspots that control protein function.

Natural hotspot target

Unique Properties of Natural Hotspots

Natural hotspots have intrinsic characteristics that make them hard for industry to drug, explaining why these pockets remain largely unexploited. Nature hotspots are:


Out of the many pockets in a protein, few are decisive in protein function and many are not visible in crystal structures. HotSpot’s technology uncovers invisible pockets and enriches for the sites that drive protein function.


Natural hotspots are not present in certain protein conformations, reducing the likelihood that chemical screening campaigns will succeed. A specialized pharmacology and in silico toolkit is required to identify compounds that bind these pockets.


Existing chemical libraries built around active sites are poorly aligned with the pharmacological footprint of natural hotspots. To successfully drug natural hotspots, new chemical scaffolds are required, powered by state of the art screening technologies.

Our process

HotSpot Therapeutics’ Smart Allostery™ platform is the first technology platform designed to systematically identify natural hotspots and enable the design of potent, selective allosteric modulators.

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

Smart Allostery™ has three key elements – SpotFinder™ to Uncover, HotSpot Toolkit to Capture and Tailored Chemistry to Drug – offering unique dry lab-wet lab integration under one roof.

SpotFinder™ to Uncover

A suite of proprietary ML/AI algorithms are trained to identify the fingerprints of natural hotspots in proteins. HotSpot’s computational platform enables full annotation of target class-derived pocketomes with respect to structure-function and site druggability. Clustering pockets on the basis of evolutionary origin generates deep insights across related proteins, while providing an entry point to selective small molecules.

HotSpot Toolkit to Capture

A toolkit of pharmacology and in silico assays stabilize specific protein-pocket conformations to display the often transient regulatory sites in an open and accessible state. High-affinity regulatory peptides can then be used as molecular screening tools to accelerate lead identification.

Tailored Chemistry to Drug

Custom chemical libraries are produced based on the 3D pharmacological footprint of natural hotspots. Using an in-house DNA-encoded library (DEL) platform, HotSpot Therapeutics has produced over 800 million compounds, establishing the industry’s most diverse hotspot- targeted chemical collection. Hit mining using ML/AI and structure-based algorithms accelerates both hit finding and chemical diversification.

Smart Allostery™ is being leveraged across entire target classes to speed pipeline development and value creation. To date, our platform has reproducibly drugged sought-after targets across three protein classes including protein classes including kinases, transcription factors and E3 ligases.