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3:41 PM
 | 
Jun 20, 2019
 |  BC Innovations  |  Targets & Mechanisms

Moving beyond the active site: why allostery is newly in fashion

How a new class of biotechs is turning allostery from serendipitous to systematic

A new crop of companies is creating tools to systematize development of allosteric protein inhibitors, finally moving industry beyond the one-off compounds that have been found by accident.

Allosteric pockets on proteins have long been viewed as promising alternatives to active sites for controlling protein function. The problem has been finding them.

An allosteric modulator can change a target’s shape, its ability to interact with other proteins, or its subcellular location. They can also be the only way to selectively modulate related targets that have highly similar active sites, or to modulate targets without active sites.

“Allosteric sites tend to be less well-conserved because the selective pressures are probably greater in the active site,” Mark Goldsmith, CEO and president of Revolution Medicines Inc., told BioCentury.

Allosteric modulators also have some pharmacologic advantages over active site inhibitors. They may work at lower doses because they do not normally need to compete for binding with highly concentrated endogenous ligands such as ATP, and in some cases they can induce changes to the target that have a longer-lasting effect than inhibiting its catalytic activity.

“In the past, most allosteric drugs were identified in phenotypic screens.”

Geraldine Harriman, HotSpot Therapeutics

Few allosteric modulators have reached the market, and a few dozen are in the clinic. Most of these have been identified serendipitously.

“In the past, most allosteric drugs were identified in phenotypic screens,” where the target and the mechanism of the compound that binds to it aren’t known, said HotSpot Therapeutics Inc. co-founder and CSO Geraldine Harriman.

Allosteric pockets are much less obvious than active sites, and come in a wide array of shapes and chemistries. That provides an advantage, because it means they can be exploited to selectively modulate a protein, but it makes screening for them harder.

New technologies are emerging, enabled by advances in computational capacity and in silico modeling, that provide sufficient power to predict which allosteric sites on a protein can be targeted, and how binding to different molecules will change a protein’s conformation and function.

At least five companies have been founded in as many years with platforms to develop allosteric modulators. Together they have raised over $800 million in venture funding, of which $400 million went to Relay Therapeutics Inc. (see Figure: “Allostery Fundraising”).

At least two longer-standing companies are getting into the game as well. Beactica AB was founded in 2006 as a CRO for small molecule discovery, and subsequently narrowed its focus to allostery, deciding in 2014 to develop an internal pipeline. Evotec SE has operated a business model designed around partnerships and a suite of CRO-like preclinical services since 1993; it launched its allostery platform TargetAlloMod last year.

Black Diamond Therapeutics Inc., which has raised $105 million since it launched in 2018, is harnessing allostery differently, using disease-causing mutations at allosteric sites to discover how they alter active site function, and designing active site inhibitors based on that information.

Four of the eight companies with allostery platforms entered into partnerships with pharmas or other biotechs. Four of these were announced since March 2018, and one, formed in 2016, was expanded this year (see "Partnering for Allostery").

Table: Partnering for Allostery

Companies with allostery platforms have signed at least five deals, four of which are partnerships made in the last 15 months, while the fifth was established in 2016 and expanded this year. Among these, Vividion Therapeutics...

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