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Small Molecule Drug Discovery in the Fast-Changing World of Biotechnology

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Small Molecule Drug Discovery in the Fast-Changing World of Biotechnology PHARMACEUTICAL INDUSTRY IN SWITZERLAND 601 CHIMIA 2004, 58, No. 9 Chimia 58 (2004) 601–607 © Schweizerische Chemische Gesellschaft ISSN 0009–4293 Small Molecule Drug Discovery in the Fast-Changing World of Biotechnology Serge Halazy and Matthias K. Schwarz* Abstract: Generally referred to as Europe’s largest Biotech company, Serono, with global headquarters in Geneva, has long been known for its portfolio of therapeutic proteins, which has, so far, resulted in market approvals of sev- eral recombinant products in the areas of reproductive health (Gonal-F, Luveris, Ovidrel), metabolism-endocrinol- ogy (Saizen, Serostim), neurology (Rebif), and dermatology (Raptiva). In the late 90s, Serono’s management made the strategic decision to add small molecule drug discovery to their research portfolio, with the aim of mimicking and further extending the spectrum of action of the existing protein therapeutics with orally bioavailable next-gen- eration products. As a hallmark of this new research paradigm, in late 1997, Serono acquired the GBRI (Glaxo Bio- medical Research Institute), now SPRI (Serono Pharmaceutical Research Institute), located just outside Geneva, and during the following year therein established a new, state-of-the-art Chemistry Department, with the neces- sary manpower, expertise, as well as the medicinal, analytical, and combinatorial chemistry equipment, including extensive structure- and ligand-based design capabilities. In conjunction with a somewhat smaller Chemistry De- partment previously established at Serono’s Boston-based research site SRBI (Serono Reproductive Biology In- stitute), Serono’s chemists have now been working for around five years on a variety of small molecule drug dis- covery projects. As the first small molecules emerging from these efforts have started entering human clinical trials, the present article will give an account on some of the work performed to date. Keywords: Chemokine binders · Discrete Substructural Analysis · GPCR modulators · Kinase inhibitors · Phosphatase inhibitors · Shape Similarity Analysis Introduction most universal ways in which the propaga- number of proprietary computational de- tion of the signal is controlled (i.e. switched sign methods were developed, and partly Protein therapeutics, such as hormones and on and off), consists in reversible phos- implemented in the context of an external cytokines, exert their action through specif- phorylation of given substrates (S) at spe- collaboration to construct a high-value ic receptors spanning the cell membrane cific signature sites, mediated by phospho- compound collection for primary screen- and transducing the extracellular stimuli to rylating and de-phosphorylating enzymes, ing. the inside of the cell (Fig. 1). Different su- kinases and phosphatases, respectively. perfamilies of membrane receptors are Based on this – simplified – understanding, known, including 7-transmembrane span- a number of potential strategies for phar- The Foreplay: Design and Construc- ning G-protein coupled receptors (7TM- macological intervention with small mole- tion of a Compound Collection GPCRs), receptor tyrosine kinases (RTKs), cules can be identified, including (i) com- cytokine receptors, and others, and the re- pounds binding to the protein ligand, there- The screening facilities at Serono were ceptor usage depends on the nature of the by preventing it from exerting its action, (ii) set up to accommodate a relatively small extracellular agent. Receptor activation compounds acting at the level of the recep- number of compounds (typically <100’000 leads to complex intracellular signaling tor, and functioning as agonists or antago- per screen). As a consequence, the con- events, with ingenious mechanisms ensur- nists, and (iii) compounds modulating the struction of the compound collection had to ing a correct transduction and propagation intracellular signal transduction by inhibit- rely on the acquisition of small, focused of the signal throughout the cell. One of the ing kinase or phosphatase activity (Fig. 1). sets of compounds biased towards a partic- At Serono, projects were initiated follow- ular target or a target class. In addition to ing each of those approaches, and some of the conventional approaches described in the results will be presented in the subse- the literature, two computational tools de- quent paragraphs. First, however, since veloped internally proved to be instrumen- there had been no prior history of small tal in this respect. In the first method, *Correspondence: Dr. M.K. Schwarz Serono Pharmaceutical Research Institute molecule drug discovery at Serono, a com- termed Discrete Substructural Analysis Department of Chemistry pound collection had to be established that (DSA) [1–3], a particular biological activi- 14, Chemin des Aulx was to be maximally enriched with privi- ty of a given compound is explained (and CH–1228 Plan-les-Ouates, Geneva leged chemotypes prone to produce the de- predicted) based on statistical association Tel.: +41 22 706 98 20 Fax: +41 22 794 69 65 sired biological activities on the target with the presence of two-dimensional mo- E-Mail: [email protected] classes mentioned above. To achieve this, a lecular fragments. Thus, by applying DSA PHARMACEUTICAL INDUSTRY IN SWITZERLAND 602 CHIMIA 2004, 58, No. 9 development of small molecule agonists or antagonists, thus rekindling the interest in the alternative strategy of targeting the lig- ands, rather than the receptors, for pharma- cological intervention. And indeed, small molecules have been developed that selec- tively bind to the cytokine IL-2, and shown to inhibit some of its biological actions [8][9]. In our lab, there has been a long-stand- ing interest in the biology and pharmacolo- gy of cytokines, more particularly a sub- class thereof, the chemoattractant cy- tokines, or chemokines. In thinking about potential strategies of pharmacological in- terference with the chemokine network [10][11], we identified chemokine ligand binding as an appealing, albeit not straight- forward, alternative to classical receptor an- tagonism, based on several considerations: first, the field of small molecule chemokine receptor antagonists has become very crowded in recent years [12], as researchers in the pharmaceutical industry have learned how to decipher the structural determinants required for effective receptor antagonism Fig. 1. Potential points of pharmacological intervention directed towards modulating the effects of [13]. Secondly, since some chemokines in- biologically active proteins. teract with different receptors (and vice ver- sa), new inhibition patterns and net biolog- ical effects can be achieved by blocking one to a set of compounds known to interact Strategy 1 – Targeting the Ligand: given chemokine, resembling those of (hy- with a given target (or target class), a com- Chemokine Antagonism Revisited pothetical) dual or even triple receptor an- mon 2D-molecular determinant responsible tagonists. Thirdly, as the biological effects for the biological activity can usually be The normal interaction between protein of a chemokine depend on its interacting identified, and subsequently re-used to ligands and their endogenous receptor(s) with both its receptor(s) and the gly- search databases of commercial com- can, in principle, be disrupted by agents cosaminoglycan (GAG) chains of cell sur- pounds and/or to synthesize small combi- binding either to the receptor or to the lig- face proteoglycans [14][15], a small mole- natorial libraries highly enriched with com- and, thereby preventing them from making cule binder can inhibit the overall process pounds active against that particular target a productive contact. Undoubtedly, in a of cell recruitment in several, more specific (or target class). The second computational classical Biotech environment, the latter ways, depending on where it binds on the approach, termed Shape Similarity Analy- has been (and still is) the first-line ap- chemokine surface, and hence cause differ- sis (SSA) [4][5], is an attempt to link simi- proach, whereby the blocking agent is an- ent biological and pharmacological effects. lar biological activities to similar three- other protein having a certain degree of With this in mind, an NMR-based affinity dimensional molecular shapes. Conceptu- structural complementarity to the ligand, screen was performed involving the ally based on the lock-and-key principle such as an antibody, a soluble receptor, or a chemokine RANTES and a small set of low [6], SSA provides an expedient way to gen- naturally occurring binding protein. In con- molecular weight compounds (‘fragments’) erate and visualize the envelope shapes of trast, the small molecule-based research that had been chosen with a view to maxi- all compounds present in a given set. Com- within the pharmaceutical industry has mum functional group diversity and/or paring the resulting shape distribution pat- mainly focused its attention on receptor proven propensity to pharmacological ac- terns of different compound sets known to blockade, as illustrated by the fact that to- tivity based on the Current Medicinal interact with closely related biological tar- day, around 50% of the marketed drugs are Chemistry (CMC) database. Gratifyingly, gets, a significantly higher inter-set similar- modulators (agonists or antagonists) of G- several compounds could be identified that ity was indeed noted in many cases, thus protein coupled receptors (GPCRs). From a specifically bound to RANTES with disso- providing
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