Macrocycles in Drug Discovery:Introduction

It is the aim of this volume to explore the study of macrocycles in drugdiscovery, both those of natural origin and semi-synthetic derivatives ofnatural products, and those designed and synthesized based on principles ofmedicinal chemistry. Macrocyclic molecules, herein defined as moleculeswith rings of 12-members or larger, have figured prominently in the historyof medicinal chemistry, with the most common source of these compoundsbeing from natural products. In fact, numerous macrocycles have becomeimportant drugs or have been identified as leads to marketed drugs.

Of late, interest in macrocycles and their novel architectures has increasedsignificantly as their potential for interacting with a variety of targets in-cluding kinases, ATPases, proteases, GPCRs and others has been recognized.Furthermore, as more non-classical drug targets, such as protein–proteininteractions (PPIs), are pursued in the pharmaceutical industry, macrocyclicmolecules have attracted significant attention since they offer the potentialto provide drug–protein interactions that cover a larger surface area thantraditional small molecules. This text will discuss the identification,optimization, pharmacology and synthesis of biologically active macrocycliccompounds in the context of their broad chemotype as compounds com-posed of large rings.

In the first chapter of this volume the wide variety of bioactive macrocyclicnatural products is explored, including examples of those with clinicallyvalidated anti-infective and anti-tumor activity. Many of these naturalproducts have been the subject of drug discovery efforts that have leveragedsemi-synthesis, biosynthesis and total synthesis in order to investigate oroptimize their pharmacological effects and viability as drugs. The medicinal

RSC Drug Discovery Series No. 40Macrocycles in Drug DiscoveryEdited by Jeremy Levinr The Royal Society of Chemistry 2015Published by the Royal Society of Chemistry, www.rsc.org

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chemistry of these macrocyclic natural products is interesting in itself, butlessons learned from these compounds, particularly in terms of the rela-tionship between structure and desirable physicochemical properties, arenow informing and driving the design of fully synthetic macrocyclic drugcandidates.

Macrocyclic inhibitors of the chaperone protein Hsp90 are the subject ofthe second chapter. This ATPase is an important oncology target againstwhich a variety of macrocyclic scaffolds have demonstrated activity,including the natural products geldanamycin and radicicol, and theirderivatives, as well as fully synthetic, designed macrocyclic aminobenzamidederivatives, all of which bind to the N-terminal ATP binding domain. In thiscase structural information gathered on the binding of the natural productsto Hsp90 was important for guiding the design of the fully syntheticmacrocyclic inhibitors. Macrocyclic inhibitors of the Hsp90 N-middledomain related to the penta-depsipeptide sansalvamide A are also knownand discussed in this section.

The third chapter of the volume describes the in vitro and in vivo activity ofthe natural occurring microtubule stabilizer epothilone B and its analogs.This macrocyclic natural product has been the subject of extensive medicinalchemistry research and numerous derivatives have been studied pre-clinically and clinically for oncology indications. One such compound,ixabepilone (BMS-247550; Ixempras) was approved by the FDA in 2007 forthe treatment of breast cancer.

Chapters 4 and 5 are also focused on macrocycles with potential utility asanti-cancer therapeutics. Thus, Chapter 4 describes drug discovery effortsdirected at the identification of inhibitors of a family of zinc-dependentenzymes known as histone deacetylases (HDACs). Interestingly, a variety ofmacrocyclic natural product HDAC inhibitors are known, including cyclicpeptides and depsipeptides with a diverse set of zinc-binding warheads, aswell as fully synthetic inhibitors. This epigenetic target has afforded two FDAapproved inhibitors as oncology therapeutics, one an acyclic hydroxamicacid derivative and the second a macrocyclic disulfide natural product,FK228, that undergoes reductive ring cleavage to reveal the active speciesbearing a thiol zinc chelator.

The search for macrocyclic kinase inhibitors is detailed in Chapter 5,starting from macrocyclic bisindolylmaleimide analogs of staurosporine, theinitial foray into this area thirty years ago by chemists at Lilly in search ofnovel protein kinase C inhibitors, to more recent drug discovery efforts intopotent inhibitors of CDKs, JAK2 and FLT3, among other kinases, driven bystructure-based design. The rational design of macrocyclic kinase inhibitorswith desirable, indication-specific, kinase selectivity profiles and oralbioavailability has been particularly exciting and has yielded severalmolecules now in clinical trials for the treatment of cancer andrheumatoid arthritis.

The sixth chapter of this volume explores the use of macrolides,macrocyclic lactone polyketide natural products best known for their

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antibacterial activity, for their anti-inflammatory activity. The propensity forthese molecules, exemplified by azithromycin, to accumulate in inflamedtissue and polarize macrophages is discussed in detail. In addition, acreative and exciting drug discovery approach has been taken that investigatesthe ability of macrolides to act as carriers of small molecule payloads in orderto transport them into immune cells. Thus, small molecule inhibitors withdiverse biochemical targets including p38 kinase and lipoxygenase, as well assteroidal and non-steroidal anti-inflammatories, have been conjugated tomacrolides and have demonstrated activity in in vitro assays and in vivoanimal models of inflammatory disease and cancer.

The identification and optimization of macrocyclic molecules that inhibita broad array of target classes such as proteases, G protein-coupled receptors(GPCRs), integrins and PPIs, is thoroughly reviewed in Chapters 7, 8 and 9.Chapter 7 focuses on providing background on the hugely important andcompetitive area of research surrounding the discovery and development ofmacrocyclic HCV protease inhibitors with multiple agents in clinical trialsand progressing to the market. The concept of macrocyclization as appliedto HCV protease inhibitors was driven by the seminal work from researchersat Boehringer-Ingelheim, and its translation into the optimization ofboron-containing irreversible inhibitors of this enzyme is presented. Thisis followed by an extensive review in Chapter 8 of macrocycles that targetGPCRs, both agonists and antagonists, integrin inhibitors and the rapidlyexpanding field of macrocyclic modulators of protein-protein interactions.That theme is further extended in Chapter 9 with a discussion of stapledpeptides. These fascinating macrocyclic molecules are constructed to lockpeptidic ligand molecules in an a-helical conformation, most often throughthe use of a hydrocarbon linker, for recognition by their targets. An extra-ordinary effort combining computational chemistry, structural biology,chemical biology and organic synthesis has enabled the evolution of thischemotype into one that can deliver stapled peptides with sufficient cellpenetration and in vivo exposure to advance into the clinic, as is the case forthe MDM2/MDMX antagonist ALRN-6924, being studied for the treatment ofp53-dependent cancers.

This volume concludes with two chapters that describe efforts that willtruly enable the expansion of the field of macrocyclic molecules for drugdiscovery and the treatment of disease. Chapter 10 covers ongoing efforts tounderstand the factors that affect the permeability and bioavailability ofmacrocyclic compounds and comes full circle with some of the naturalproducts described in Chapter 1. Thus, the field of medicinal chemistry has,over the last 15 years in particular, focused on deciphering the relationshipbetween the physical properties of a molecule and its oral bioavailability,since there is a great preference for small molecule drugs to have the con-venience of oral dosing. With this in mind, the natural products that do notadhere to standard Rule of Five guidelines yet do display reasonable oralbioavailability have become the subject of intense scrutiny in an attempt tounderstand how and why they are able to be orally absorbed so that those

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principles can be applied to additional molecules outside of the Rule ofFive space.

Finally, Chapter 11 provides the last piece in the puzzle for deliveringmacrocyclic molecules for drug discovery programs and advancing theminto clinical trials and ultimately to the market for the benefit of patients.Therefore, in order to optimize macrocycles for potency against a target andpharmacokinetics, to make sufficient quantities to test in animal models ofefficacy and toxicity, and to manufacture these materials on large scalefor commercial use, one needs to be able to devise and execute practical,scalable routes for their synthesis. Chapter 11 provides an exhaustive surveyof the methodologies that have been used to generate these molecules.

In summary, this volume covers a selection of the most active andpromising areas of research ongoing in the discovery of macrocycles fortherapeutic use and we hope it provides valuable insight into the challengesencountered and solved for this diverse class of molecules.

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