drug discovery and the human kinome: recent trends

Download Drug discovery and the human kinome: Recent trends

Post on 11-Sep-2016

212 views

Category:

Documents

0 download

Embed Size (px)

TRANSCRIPT

  • Drug discovery and the human kinome: Re

    Richard Eglen , Terry Reisine 1

    Bio-discovery, 940 Winter St., Waltham, MA 02451-1457, United States

    AllosterismProteinprotein iKinase translocatGrowth factor ag

    g to the catalyticprovide a numberre selective, sinceeveloped to drugsctors that inhibiturthermore, theytivity. One hurdlet proteinproteinemsof identifying

    allostericmodulators,major gains havebeenmade in identifying allosteric inhibitors and activators of the growtholuble tyrosine and serine/threonine kinases and some of these drugs are now in

    Contents

    1. Introduction . . . . . .2. Discovering small molecu3. Allosteric modulators of s

    novel a. . .. . .. . .

    Pharmacology & Therapeutics 130 (2011) 144156

    Contents lists available at ScienceDirect

    Pharmacology &

    j ourna l homepage: www.e lsev1. Introduction

    Protein kinases are a family of enzymes involved in signaltransduction in every human cell. The enzymes detect both externaland internal stimuli to cells and produce their functions by phosphor-ylating proteins. This process initiates and propagates information owto allow cells to respond to their changing environment. This family of

    Abbreviations: ATP, adenosine triphosphate; AKT, v-akt murine thymoma viraloncogene homolog; BRAF, v-raf murine sarcoma viral oncogene homolog B1; BDNF,

    brain-derived neurotrophic factor; CNS, central nervgrowth factor; EPO, erythropoietin; ERK, extracellular-Frster resonance energy transfer; IL, interleukin; Jtransducer and activator of transcription; MAP kinakinase; NGF, nerve growth factor; NMR, nuclear magnephosphoinositide-dependent kinase-1. Corresponding author at: Bio-discovery, PerkinElme

    02451-1457, United States. Tel.: 781 663 5599; fax: 781E-mail address: richard.eglen@perkinelmer.com (R.

    1 Terry Reisine, PhD is an independent consultant.

    0163-7258/$ see front matter 2011 Elsevier Inc. Aldoi:10.1016/j.pharmthera.2011.01.007References . . . . . .4. Assays to discover5. Summary . . . .Acknowledgments . . 2011 Elsevier Inc. All rights reserved.

    . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144les that act like large proteins . . . . . . . . . . . . . . . . . . . . . . . . . 145oluble protein kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146llosteric modulators of protein kinases . . . . . . . . . . . . . . . . . . . . . 148. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

    144145149153154154154proteins is essenleads to abnorma

    The protein kthe pharmaceut2009, 2010). A laclinical developmto treat a widediabetes, immun

    ous system; EGF, epidermalsignal-regulated kinase; FRET,AK-STAT, Janus kinase-signalse, mitogen-activated proteintic resonance; PDK1, PDK1, 3-

    r, 940Winter St., Waltham, MA663 5984.Eglen).

    l rights reserved.een employed to identify such compounds.

    various stages of clinical trials. This review will focus on the discovery of novel allosteric modulators of proteinkinases and drug discovery approaches that have bfactor receptors as well as sto overcome in discovering tinteractions; generally difcunteractionsiononists/antagonists

    compounds differ from ATP-centric drugs in that they do not compete with ATP for bindindomain, generally acting by inducing conformational changes tomodulate activity. They couldof advantages over more classical protein kinase drugs. For example, they are likely to be mothey bind to unique regions of the kinase andmay be useful in overcoming resistance that has dthat compete with ATP. They offer the ability of activating the kinases either by removing fakinase activity or by simply producing changes to the enzyme to foster catalytic activity. Fprovidemore subtlemodulation of kinase activity than simply blocking ATP access to inhibit ac

    hese compounds is that allosteric modulators may need to inhibilt to accomplishwith smallmolecules. Despite the technical problA major new trend in drugs targeted at protein kinases is the discovery of allosteric ma b s t r a c ta r t i c l e i n f o

    Keywords: odulators. Thesecent trends

    Therapeutics

    i e r.com/ locate /pharmtheratial for normal physiology and when dysfunctionall cellular activity and disease.inase family is a major target for drug discovery byical industry (Simpson et al., 2009; Eglen & Reisine,rge number of protein kinase inhibitors are either inent or have been approved for marketing by the FDAvariety of diseases including cancer, inammation,odeciency and CNS disorders (see Eglen & Reisine,

  • 145R. Eglen, T. Reisine / Pharmacology & Therapeutics 130 (2011) 1441562009, 2010). Many of these drugs have improved survival and qualityof life of cancer patients as well as in individuals suffering from othercomplications.

    In general, kinase inhibitors have been classied into four differenttypes based on their mechanisms of action (see Zhang et al., 2009;Eglen & Reisine, 2010). Type 1 inhibitors work via a classicalmechanism of action to block the access of ATP to the catalyticdomain of the kinase in a competitive manner. Type 2 inhibitorsinteract with kinases in a somewhat different manner, specicallybinding to the inactive form of the kinase to prevent the activationprocess, much in the manner of Gleevec. Type 3 inhibitors, which willbe the major focus of this review act via allosteric sites to block theactivity. As dened by Zhang et al. (2009) and others, allostericmodulators interact with A site distinct from the enzyme active site...[to] regulate[s] enzyme activity. This can mean interacting with sitesnear the active site but not within the catalytic domain or more distalsites such as regions involved in the regulatory subunit interactionwith the catalytic domain of the cAMP dependent protein kinase, oreven the growth factor binding sites on the N-terminal transmem-brane domain receptors that affect conformational changes in the C-terminal catalytic domain to affect enzyme activity. Thus, allosterismencompasses a large gamut of mechanisms of kinase regulation.Finally, type 4 inhibitors are primarily covalent inhibitors of kinasesthat target active sites.

    While much of the classical discovery of the protein kinase drugshas targeted regions around the ATP binding sites to identifyinhibitors, emerging trends have focused on identifying allostericmodulators. The interest in developing allosteric modulators is thatsuch drugs may provide unique advantages over more classicallydeveloped compounds (Li et al., 2004; Noble et al., 2004; Zhang et al.,2009; Eglen & Reisine, 2009, 2010).

    First, they offer the possibility of greater selectivity because theytarget sites in kinases more unique in sequence and structure thanthose compounds that bind to the regions near the ATP bindingdomain, which are generally more conserved amongst proteinkinases. Greater selectivity might be expected to reduce the side-effects compared to the more pervasive kinase inhibitors. Theselectivity of the allosteric modulators can also provide approachesto differentially regulate the subtypes of a kinase within a subfamily,which may have similar or the same substrates and high overallsequence similarity.

    Secondly, allosteric modulators hold a promise in selectivelytargeting mutant forms of disease causing protein kinases and inovercoming resistance of the kinases to the ATP binding competitivedrugs. As described elsewhere (Cohen, 2002; Bardelli et al., 2003;Dancy & Sausville, 2003; Noble et al., 2004; Pearson et al., 2006; Zhanget al., 2009), many diseases, notably proliferative diseases such ascancer, are caused in part or completely by mutations that generateconstitutive kinase activity. The mutations can change the conforma-tion of the kinase and drugs that selectively interact with the mutantform of the kinase may block the activity of the disease causingenzyme while having less or no effect on the natural form of enzymepreserving normal function.

    For example, this has been shown to be the case for the serine/threonine kinase BRAFV600E which causes almost half of the malignantmelanomas and is the most common disease causing mutant kinase(Tsai et al., 2008). The mutation causes constitutive activity of thekinase and continuous stimulation of the downstream MAPkinase/ERK signaling pathway. The small molecule drug PLX4032 (see Fig. 1for structure) selectively inhibits BRAFV600E and is much less potentagainst the wild type kinase or any other kinase and blocks theMAPkinase/ERK signaling pathway only in cells expressing themutant kinase both in vitro and in vivo. This drug selectively targetsthe disease causing kinase providing an incredible level of specicityover any other protein in the body and this drug. PLX4032 is currently

    being tested in the clinic and has shown great promise in treatingmelanomas which have previously not been effectively treated byother drugs (Flaherty et al., 2009). While this drug is not allosteric inaction, the allosteric inhibitors are more likely to show this prolebecause in general they are much more selective in targeting kinasespecic conformations than the more classical ATP competitiveinhibitors.

    Thirdly, while most of the drug discovery activities against proteinkinases have focused on identifying the inhibitors of kinase activityand ATP binding, allosterism allows for the identication ofcompounds that could result in activators of kinases. This may beparticularly relevant for the family of receptor kinases such as thegrowth factor receptors, where binding of large proteins to theextracellular domains induces conformational changes that activatethe intracellular catalytic ac

Recommended

View more >