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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

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