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Recent Advances in Drug Discovery of GPCR Allosteric Modulators Recent Advances in Drug Discovery of GPCR Allosteric Modulators ADDEX Pharma S.A., Head of Core Chemistry Chemin Des Aulx 12, 1228 Plan-les-Ouates, Geneva, Switzerland Jean-Philippe Rocher, PhD results in a number of differentiating factors. In fact, most Introduction allosteric modulators have little or no effect on receptor function until the active site is bound by an orthosteric The importance of the allosteric regulation of cellular ligand. Allosteric modulators therefore have multiple functions has been known for decades and even the word potential advantages compared to small molecule and “allosterome,” which describes the endogenous alloste- biologic orthosteric drugs. In particular, they offer new ric regulator molecules of a cell, has been proposed 1. chemistry possibilities allowing access to well known tar- Although best described as modulators of enzymes, gets that have been considered intractable to historical advances in molecular biology and robotic HTS technolo- small molecule approaches. For example, allosteric mod- gies recently allowed the discovery of small molecule allo- ulators may soon be developed for targets which hereto- steric modulators of various biological systems, including fore have been only successfully targeted with proteins GPCR and non-GPCR targets. Today, allosteric modula- and peptides. In other words, allosteric drugs with all the tors appear to be an emerging class of orally available advantages of small molecules － brain penetration, eas- therapeutic agents that can offer a competitive advantage ier manufacturing, distribution and oral administration over classical “orthosteric” drugs. This potential stems - may soon be viewed as the best life cycle management from their ability to offer greater selectivity and differ- strategy for protein therapeutics 2. Another potential ben- entiated control over disease mediating receptors. Most efit of allosteric drugs compared to orthosteric drugs is marketed drugs bind to receptors where the body’s own the greater ease of achieving higher selectivity for the tar- natural molecular activators (i.e. endogenous ligands) get. The allosteric sites, unlike the orthosteric sites, have bind specifically to a key part of each receptor’s anatomy been shown to display greater heterogeneity, in all like- called the “active site”. Orthosteric ligands are natural or liness because they have evolved with less evolutionary therapeutic molecules － including peptides and proteins pressure compared to the active sites, especially among － which bind to the active site of receptors. By contrast, closely related receptors that may share a common allosteric modulators bind to receptors at a different site endogenous ligand. In the case of metabotropic receptors and modify receptor function even if the endogenous for example, the glutamate binding orthosteric site is very ligand also binds to the active site at the same time. As a well conserved within 8 members of the family, rendering result, allosteric modulators are non-competitive, which the task of making subtype selective compounds highly MEDCHEM NEWS No.3 AUGUST 2011 .7 challenging. Allosteric compounds discovered and devel- wide range of effects, starting with a change of the recep- oped in recent years have been shown to offer exquisite tor conformation from an inactive to an activated state. selectivity for one subtype vs other receptors of the same This leads to activation of the receptor associated with family (as well as other families). G-protein and initiates intracellular signaling cascades Allosteric drug discovery has been recently the topic of that mediate cellular responses. Allosteric modulators are increased interest, adressing various important target thought to stabilize or induce changes in the receptor classes besides G-protein coupled receptors (GPCRs): state causing a shift in their responsiveness to endoge- proteases 3, kinases 4, 5, phosphodiesterases 6 and ligand- nous ligands. gated ion channels 7. Allosteric Modulators of GPCRs: Mechanism of Action and Detection GPCRs are the largest family of integral membrane recep- tors; the ubiquitous distribution of GPCRs and their involvement in virtually all physiological processes make them extremely attractive targets for drug development. Allosteric modulation as a potential solution for the most challenging receptors in this class has been the topic of recent reviews 8, 9, 10. Allosteric modulators of GPCRs inter- act with binding sites that are topographically distinct from binding sites of the endogeneous ligands (see Figure 1． Negative Allosteric Modulators diminish the signal of a Figure 1). Furthermore, positive allosteric modulators membrane-spanning GPCR. Positive Allosteric Modulators boost it. (PAM) generally do not activate receptors in the absence of an orthosteric ligand. In the presence of orthosteric Biophysical methods such as surface plasmon resonance ligand, PAM enhance the natural physiological activity of (SPR) and NMR that directly measure the GPCR-ligand the receptor imposing a “ceiling” at the magnitude of interaction have been investigated 11, 12, 13 in particular their allosteric effect; this property will limit the adverse for fragment based drug discovery (FBDD). These effects and also the desensitization that might be pro- approaches and the emerging structural biology technol- duced by an orthosteric agonist. Thus, by applying a non- ogies could be complementary biological methods, which competitive approach that is both more selective and, at may be useful for obtaining information on molecular the same time, able to preserve the physiological rhythms interaction. of endogenous ligand-GPCR signaling, it may be possible to show that therapeutic agents are safer than conven- The tools used to identify allosteric modulators have ben- tional competitive agonists or antagonists against the efited from modern molecular biology techniques such same targets. as complex cell engineering allowing functional expres- In addition, allosteric ligands have been identified that sion of targets of interest 14. Fluorescence-based assays bind to an allosteric site with high affinity without affect- measuring secondary messengers such as calcium ing the receptor function. These molecules are referred (Ca++) or cyclic adenosine monophosphate (cAMP) are to as neutral allosteric modulators or silent allosteric widely used in GPCR drug discovery. The miniaturization modulators (SAM). of the assay format from 96- to 384- and even 1536- to Binding of GPCRs by their endogenous ligand triggers a 3072-well plates and technological developments for assay 8. MEDCHEM NEWS No.3 AUGUST 2011 Recent Advances in Drug Discovery of GPCR Allosteric Modulators readouts have made the screening of large corporate pharmacological profile of the allosteric molecule. chemical libraries in high throughput mode possible. Modulation of the functional activities of allosteric modu- However, conventional high throughput screening (HTS) lators by minor structural changes has been observed assays show a number of limitations. Firstly, most of these within several series, in particular with mGluR allosteric assays are endpoint assays, and completely ignore ligands 16. Figure 2 shows several examples of “PAM- dy namic changes linked to receptor activation. Secondly, NAM switches” in the mGluR5 ethynyl pyridine series. In most assays include a long incubation and/or revelation this MPEP series, partial and silent allosteric ligands of time, allowing potentially non-specific binding of candi- mGluR5 have been discovered. These molecules are dif- date compound to cellular components other than the ferentiated by the position of the methyl substituent on targeted receptor; and, finally, the signal measured is sev- the pyridine ring. 5-Methyl-6-(phenylethynyl)-pyridine eral steps removed in the signaling cascade, allowing (5MPEP) is a neutral allosteric ligand and it displaces potential up- or down-modulation of every step, leading to [3H]-3-Methoxy-PEPy from the MPEP binding site with a a loss of linearity between initial level of activation of Ki = 388 nM while exhibiting no functional response on receptor and the level of output measured. As a result of its own. 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine these factors, the potential for false positive and negative (M-5MPEP) is a partial antagonist and as such is partially in such assays is unacceptably high for successful alloste- inhibiting the functional response of the mGluR5 recep- ric drug discovery. tor to the glutamate. Such a profile, exhibiting activities At Addex we have developed proprietary novel whole-cell along the continuum between activation and antagonism assays that address the above issues. For example, the has only been described for allosteric modulators. ProxyLiteTM assay was designed to detect allosteric mod- Orthosteric antagonists are essentially binary in their ulatory activity with greater sensitivity than conventional functionalities and cannot function as partial antagonists. assays. It allows real-time dynamic measures of receptor A continuum of efficacy switching in a related series of activation by measuring signals that occur during the ethynyl pyridine carboxamides is also reported 17 (Figure receptor activation event 15. ProxyLite therefore bypasses 2). the downstream screening cascade and reduces potential of false positives and, perhaps more importantly, has revealed false negatives that occur during screening cam- paigns with less sensitive tools. At the same time, ProxyLite
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