MASTER REGULATORS OF GENE EXPRESSION
A transcription factor reads the genome and orchestrates its expression by integrating accessory proteins at specific regions of DNA.
© 2021 FLARE THERAPEUTICS. ALL RIGHTS RESERVED.
SUPREME
DRUG
TARGETS
Transcription factors (TFs) have long been the aspirational targets of drug developers, based on their central role in cancer and other diseases.
What are TFs
TFs are DNA-binding proteins that can activate or repress DNA transcription and, therefore control gene expression.
Why they matter
As drug targets, TFs differ from many other target classes by offering a powerful blend of exquisite potency with highly selective cellular activity.
THE LARGEST PROTEIN FAMILY:
TF MUTATIONS CAUSE:
ELUSIVE
FOR
DECADES
Despite a broad consensus around their role in disease and vast therapeutic potential, transcription factors have been elusive targets for drug discovery.
- <1% of TFs have been successfully targeted for therapeutics.
- Targeting of TFs has previously been limited by the inability to systematically link their biochemical function to targetable sites for small molecule drug discovery.
A FLARE
OF
INSPIRATION
Setting the stage
Flare’s scientific co-founders have decades of experience understanding the biology and structure of TFs. Their seminal work includes elucidating molecular mechanisms for targeting TFs with ligands and structure-function relationships of TF complexes.
The spark ignites
As early members of the Flare team were building a company focused on transcription factors, they were inspired by the work of Dr. Fraydoon Rastinejad of Oxford University on the HIF2A transcription factor. Now one of Flare’s scientific co-founders, Dr. Rastinejad had elucidated the structural basis for bidirectional tuning of gene regulation by HIF2A using small molecules. The Flare team recognized the broad potential for the key principles that emerge from this work to be generalizable across TFs through a new paradigm they called “switch sites.”
MASTER REGULATORS OF GENE EXPRESSION
A transcription factor reads the genome and orchestrates its expression by integrating accessory proteins at specific regions of DNA.
........
THE HISTORICALLY NARROW VIEW MAKES TFs ELUSIVE
Significant efforts have been made to target transcription factors because of their central role in disease. However, these efforts have focused on individual transcription factor domains in isolation. This reductionist framework obscures the most crucial aspects of TF biochemistry.
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AN APPRECIATION OF THE COMPLEX CHOREOGRAPHY
Precise gene control requires cooperative communication and allosteric interaction among the elements of the transcription machinery. Taking an approach that reflects the cooperative nature of TFs reveals new insights and therapeutic opportunities.
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AN APPRECIATION OF THE COMPLEX CHOREOGRAPHY
Precise gene control requires cooperative communication and allosteric interaction among the elements of the transcription machinery. Taking an approach that reflects the cooperative nature of TFs reveals new insights and therapeutic opportunities.
........
LINKING FORM TO FUNCTION
By understanding the interactions within the transcriptional complex and mapping them onto three-dimensional structures, Flare deciphers the biochemical and structural mechanisms that regulate transcription.
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ILLUMINATING THE SWITCH SITE
Previously hidden – but now revealed – within certain transcriptional complexes is a druggable pocket that contains amino acid residues whose position is critical to the structural and functional integration of the complex. The pockets that contain these decisive amino acids are what we at Flare have identified as switch sites.
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FLARE’S DRUG DISCOVERY & DEVELOPMENT
Based on a fundamental understanding of the cooperative biochemistry of the TF complex, Flare uses the best tools and technologies to discover small molecule modulators of TF function at the switch site.
OUR DRUG DISCOVERY PROCESS
Switch site identification
Switch site ID is guided by genetics, chemoproteomics and structural biology. One such example resulted from mapping a cluster of rare genetic disease mutations in a particular TF onto the structure of its multi-component complex to reveal that the mutations completely outline a novel and unexplored pocket, suggesting a potential switch site.
Switch site ligandability
With knowledge of the switch site, we utilize our cooperative biochemical systems coupled with the latest, state-of-the-art hit-finding approaches to assess ligandability
Switch site pharmacology
Following evidence of ligandability, we next leverage emerging transcriptomic and epigenomic technologies to relate our biochemical read-outs to the cellular context. It is the faithfulness of this cross-talk that both confirms the validity of our assays and facilitates optimization of differentiated pharmacology to enable Flare’s new class of TF-targeted medicines.
OUR Technologies & Tools: adapted to the switch site realm
- Biochemical and biophysical tools that measure conformation
- Chemoproteomics
- Structural biology
- Computational screening
- Proprietary cellular assays designed for chemical biology strategies
- Single cell epigenomics