※LABIOTECH.eu: Pinning Down Elusive Targets: Interviewing the Co-Founder & CSO of Heptares.
17/07/2017
Heptares is expanding into a range of indications with its GPCR platform. I caught up with CSO & co-founder Fiona Marshall to hear more about the strategy.
Fiona Marshall has always worked on G-protein coupled receptors, or GPCRs for short. These entities are key to many eukaryotic signaling pathways, and because of their prevalence, they’re the targets of roughly 40% of modern medicines.
After finishing her PhD on neuropeptide receptors, Marshall continued her work at GSK, Millennium and then as an independent consultant.
When she went to analyze work to stabilize GPCRs at the MRC Laboratory of Molecular Biology, Marshall crossed paths with a former colleague, Malcolm Weir, and together with the scientists at the LMB, they founded the company that has risen to become the dominant player in the GPCR space: Heptares Therapeutics.
“We have dabbled in other membrane proteins — certainly, the technology can apply to others,” Marshall told me.
“But, primarily, Heptares is still very much focused on GPCRs, because they’re such a huge target class: there’s so much opportunity there.”
The prevalence of GPCRs means that a number of companies are working on drugs that target individual receptors, but the GPCR space as a whole is relatively unpopulated by biotechs.
Besides Confo Therapeutics, a startup we heard pitch at Refresh last month, Heptares has no real competitors when it comes to the structural biology of GPCRs. Although many companies have drugs that work through GPCRs in their pipelines, these are not usually discovered using structure-based design.
“There’s a lot of data showing that compounds that have come out of high-throughput screens aren’t properly optimized for the target,” Marshall said.
“They often have off-target effects, which can be hitting other targets or unexpected toxicity. There are quite a few papers that show that compounds coming out of a structure-based design with optimized molecular properties have lower attrition and higher success rates.”
That’s where Heptares has found a foothold: with its focus on GPCR structure, the company has developed a platform called StaR to stabilize these tricky receptors, identify the best conformations of the receptors and design drugs to fit them.
“We introduce a small number of mutations into the receptor that help to maintain the proper shape and conformation of the GPCR when it’s taken out of the cell and put it in a detergent environment for crystallization,” Marshall explained.
“We’re using a whole range of different computational approaches including molecular dynamic simulations, which model the movements of proteins,” she continued.
These programs study the receptors’ behaviors in a cell’s lipid bilayer and in the presence of a drug. “We then use computational methods to design even better drugs that perfectly fit the pockets in the receptor protein,” Marshall explained.
Then, the company re-inserts the receptors into the cells to ensure that the induced mutations don’t alter ligand binding.
Finally, the designer compounds are then tested in normal receptors, both in cells and disease-relevant tissues.
She believes the company holds a unique position in the space because of its comprehensive approach to GPCRs.
Drug design is just the first part of the package: “We’re also using innovative translational strategies as we progress through the clinic, and because of that, I don’t think we really have any direct competitors,” she said.
※LABIOTECH.eu: Pinning Down Elusive Targets: Interviewing the Co-Founder & CSO of Heptares.
17/07/2017
Heptares is expanding into a range of indications with its GPCR platform. I caught up with CSO & co-founder Fiona Marshall to hear more about the strategy.
Fiona Marshall has always worked on G-protein coupled receptors, or GPCRs for short. These entities are key to many eukaryotic signaling pathways, and because of their prevalence, they’re the targets of roughly 40% of modern medicines.
After finishing her PhD on neuropeptide receptors, Marshall continued her work at GSK, Millennium and then as an independent consultant.
When she went to analyze work to stabilize GPCRs at the MRC Laboratory of Molecular Biology, Marshall crossed paths with a former colleague, Malcolm Weir, and together with the scientists at the LMB, they founded the company that has risen to become the dominant player in the GPCR space: Heptares Therapeutics.
“We have dabbled in other membrane proteins — certainly, the technology can apply to others,” Marshall told me.
“But, primarily, Heptares is still very much focused on GPCRs, because they’re such a huge target class: there’s so much opportunity there.”
The prevalence of GPCRs means that a number of companies are working on drugs that target individual receptors, but the GPCR space as a whole is relatively unpopulated by biotechs.
Besides Confo Therapeutics, a startup we heard pitch at Refresh last month, Heptares has no real competitors when it comes to the structural biology of GPCRs. Although many companies have drugs that work through GPCRs in their pipelines, these are not usually discovered using structure-based design.
“There’s a lot of data showing that compounds that have come out of high-throughput screens aren’t properly optimized for the target,” Marshall said.
“They often have off-target effects, which can be hitting other targets or unexpected toxicity. There are quite a few papers that show that compounds coming out of a structure-based design with optimized molecular properties have lower attrition and higher success rates.”
That’s where Heptares has found a foothold: with its focus on GPCR structure, the company has developed a platform called StaR to stabilize these tricky receptors, identify the best conformations of the receptors and design drugs to fit them.
“We introduce a small number of mutations into the receptor that help to maintain the proper shape and conformation of the GPCR when it’s taken out of the cell and put it in a detergent environment for crystallization,” Marshall explained.
“We’re using a whole range of different computational approaches including molecular dynamic simulations, which model the movements of proteins,” she continued.
These programs study the receptors’ behaviors in a cell’s lipid bilayer and in the presence of a drug. “We then use computational methods to design even better drugs that perfectly fit the pockets in the receptor protein,” Marshall explained.
Then, the company re-inserts the receptors into the cells to ensure that the induced mutations don’t alter ligand binding.
Finally, the designer compounds are then tested in normal receptors, both in cells and disease-relevant tissues.
She believes the company holds a unique position in the space because of its comprehensive approach to GPCRs.
Drug design is just the first part of the package: “We’re also using innovative translational strategies as we progress through the clinic, and because of that, I don’t think we really have any direct competitors,” she said.
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