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Rhythm and Blues: The Case for Allosteric Modulators

Switzerland’s Addex Pharmaceuticals rides optimism after drug setback.

May 18, 2010 | The vast majority of drugs on the market act by competing directly with the target’s natural ligand for the protein’s active site. But a handful of marketed molecules—Amgen’s hyperparathyroidism drug cinacalcet and Pfizer’s HIV inhibitor maraviroc are two examples—show the potential of a new class of drugs: allosteric modulators.

By targeting other regions of a receptor or enzyme, allosteric modulators offer a more nuanced method of boosting or dialing down the activity of the protein target. “Allosteric modulators act like a dimmer switch—you’re modulating the intensity of the biological response,” says Robert Lütjens, director of core biology at Switzerland’s Addex Pharmaceuticals.

Addex was founded in Geneva in May 2002. Co-founder and CEO Vincent Mutel was formerly head of CNS pharmacology at Roche. Lütjens, one of the founding scientists, leads development of the high-throughput screening program and assays used to identify and optimize the lead molecules. Addex’ early idea was to identify blockers for mGluR5 (metabotropic glutamate receptor 5), focusing on negative modulators to treat addiction—hence the company name. The platform has since been extended to other G-protein-coupled receptors (GPCRs) and other targets, including cytokine receptors.

The concept of allosteric modulation has been around since the 1960s, notably with the benzodiazepines, but Addex may be the only company exclusively developing them. “We’ve developed assays for identifying small molecules that bind into those [allosteric] sites and block or enhance the activation of the receptor,” says Lütjens. Allosteric modulators can bind to the extracellular (or transmembrane) portion of the receptor and modulate the signal that is transduced inside the cell. “We’re just enhancing the response or increasing the affinity of the receptor, or blocking the transduction into the cell.”

Unlike traditional small molecules, which turn the response on or off regardless of the release of natural ligand, Lütjens says allosteric modulators “preserve the natural rhythm of the response. Because if you add an allosteric modulator to a receptor alone, you don’t see a response. Only in the presence of the natural ligand do you observe a modulated response.” In other words, the body retains an element of control while the modulator works to normalize the signaling.

Good Concept

Allosteric modulators offer many advantages, says Lütjens, beyond respecting the rhythm of the biological system. Lütjens also highlights greater specificity. Many drug targets exist in closely related protein families, presenting the likelihood for promiscuous binding of lead compounds. By focusing on allosteric modulation, compounds bind to sites that have been under much less evolutionary selective pressure. “Because of differences between different receptors, even in same family, the sequence at the allosteric site is much more different from one receptor to another compared to the natural ligand’s binding site; so we can achieve very high selectivity and specificity.” Less off-target activity may mean fewer un-intended effects.

Other perks are that the lead optimization phase can be faster. Lütjens estimates Addex can save up to 6-12 months compared to traditional programs. Moreover, “we’re not obliged to replace ligand,” says Lütjens, which in some cases is a large peptide not easily replaceable by a conventional small molecule.

Addex works from a library of more than 70,000 small molecules. While the physicochemical properties of these compounds resemble traditional small-molecule drugs, there are some general structural differences in terms of their chemical space, which opens up new intellectual property possibilities. “There are lots of distinct properties but I’m not sure I can disclose them,” says Lütjens coyly.

Most of Addex’ compounds—about 60%—are filtered from commercial sources. Another 30% come from non-commercial sources or other industries. Finally, about 10% of the compounds are novel, synthesized in house. The filters are designed to make druggable compounds, good starting points for chemical modification during lead optimization.

In addition to the library construction, Lütjens says that Addex’s screening assays provide a significant advantage to specifically identify allosteric modulators. Much of Lütjens own work focuses on improving or developing new assays, because conventional GPCR activity assays—methods based on detecting levels of calcium or cyclic AMP—turn out to read proteins lying downstream of the receptor. Several proprietary assays, such as Phoenyx, can measure cAMP levels in living cells in a dynamic fashion. Lütjens also notes that more and more GPCR proteins are being crystallized lately, providing valuable structural data.

Despite the considerable potential of allosteric modulation, last year, Addex withdrew its most advanced clinical drug candidate, a migraine therapy called ADX10059, which Lütjens conceded was very disappointing. Like their more common “orthosteric” counterparts, allosteric modulators are still small molecules with sometimes unpredictable toxicity profiles in man.

Still, Addex has a broad pipeline, including central nervous system, metabolic disease, and inflammation, with short-term hopes resting on ADX48621, a Parkinson’s drug. Of 14 disclosed programs in development, Addex has partnered three, one with Johnson & Johnson and two with Merck in Parkinson’s disease and schizophrenia, focusing on mGluR 4 and 5, respectively. The Johnson & Johnson partnership, which began in 2004, is targeting the mGluR2 receptor, with a drug candidate, ADX71149, in the clinic for anxiety and schizophrenia—the first positive allosteric modulator targeting any mGluR to be tested in humans.

This article also appeared in the May-June 2010 issue of Bio-IT World Magazine.
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