Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity

Zapf, Christoph W.; Bloom, Jonathan D.; McBean, Jamie L.; Dushin, Russell G.; Nittoli, Thomas; Otteng, Mercy; Ingalls, Charles L.; Golas, Jennifer M.; Líu, Hao; Lucas, Judy; Boschelli, Frank; Hu, Yongbo; Vogan, Erik; Levin, Jeremy I.

doi:10.1016/j.bmcl.2011.03.112

Cited by 18 publications

(12 citation statements)

References 22 publications

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“…[220][221][222][223] The best of these molecules not only displayed good binding and functional activity, but also high solubility and an acceptable microsomal stability profile. …”

Section: Buchwald-hartwigmentioning

confidence: 98%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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“…[220][221][222][223] The best of these molecules not only displayed good binding and functional activity, but also high solubility and an acceptable microsomal stability profile. …”

Section: Buchwald-hartwigmentioning

confidence: 98%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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“…This liability was addressed by the design of amide linkers (Figure 2.15), thereby removing the basicity of the linker nitrogen. 136 Thus, lactam 35 has moderate Hsp90 enzyme activity (IC 50 ¼ 214 nM) and sub-micromolar cell proliferation activity (HCT 116 EC 50 ¼ 815 nM). It is notable that even with the significant linker rigidification through the incorporation of the amide, the angular methyl group in 35 is required for potency, as the corresponding desmethyl analogue is more than 30-fold less potent in the Hsp90 binding assay.…”

Section: Class Iii: Macrocyclic O-aminobenzamides and Aminopyrimidinesmentioning

confidence: 99%

“…A more potent analogue could be obtained by appending a methyl group on the carbon next to the basic amine of the linker to give 33 with a binding IC 50 of 91 nM and an HCT116 EC 50 of 43 nM (geldanamycin HCT116 EC 50 ¼ 30 nM), while maintaining the solubility and microsomal stability of 32. 136 A variety of analogues in which an additional ring was fused to the macrocycle were also prepared in an effort to further rigidify the macrocycle linker and impact potency. 137 For example, pyrrolidine derivative 34 (Figure 2.14) has a binding IC 50 of 96 nM and an EC 50 of 30 nM in the HCT116 cell proliferation assay.…”

Section: Class Iii: Macrocyclic O-aminobenzamides and Aminopyrimidinesmentioning

confidence: 99%

Recent Advances in Macrocyclic Hsp90 Inhibitors

Ramsey

Kitson

Levin

et al. 2014

Macrocycles in Drug Discovery

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Natural products were the first compounds to confirm the advantages of cyclised structures, where the ring conformation provides structural stability and chemical potency. Successful clinical applications of macrocyclic compounds in oncology have produced powerful incentives within the medicinal chemistry community to explore macrocyclic drug candidates that target novel oncogenic pathways. Numerous receptors, signalling molecules, and enzymes involved in oncogenesis require the chaperone activity of heat shock protein 90 (Hsp90), an ATPase-driven dimer whose chief molecular roles involve protein folding and stabilisation. Herein we describe four classes of macrocyclic Hsp90 inhibitors. Class I macrocyclic anticancer agents, currently in clinical trials, target the ATP-binding pocket of Hsp90 and include synthetic derivatives of the ansamycin antibiotic geldanamycin (17-AAG or tanespimycin, 17-DMAG or alvespimycin, IPI-504 or retaspimycin). Class II inhibitors (radicicol, radanamycin), which also target the ATP-binding pocket of Hsp90, demonstrate greater potency than Class I inhibitors in preclinical studies, and recent improvements incorporated into synthetic derivatives and chimeras have led to greater structural stability than class I without loss of potency. Class III features synthetic derivatives targeting Hsp90's ATPase activity (o-aminobenzamides and aminopyrimidines), with promising clinical data pointing to these scaffolds as the next generation of therapeutic Hsp90 inhibitors. Class IV compounds are allosteric inhibitors that bind to the N-middle domain of Hsp90 and block access to proteins that bind the C-terminus of Hsp90 (SM122 and SM145). This final class is unique as it does not target the ATP binding site of Hsp90, thereby avoiding induction of the heat shock response. Development of compounds that modulate Hsp90's C-terminus may prove to be an effective method of avoiding the rescue response mounted when blocking the ATP-ase activity of Hsp90.

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“…Pfizer scientists described the synthesis of tetrahydroindolone-containing macrocycles to target Hsp90 inhibitors. [89][90][91][92] In an effort to synthesise analogues of biologically active macrocycles, Heckrodt et al developed a synthetic strategy to efficiently generate 17-membered rings in a small number of steps (see Figure 13). 99 In the 'build' phase, peptidic building blocks containing an allyl glutamine derivative (13-1) were synthesized with the aim of a RCM macrocyclization strategy.…”

Section: Algorithmic Strategies 21 Build/couple/pairmentioning

confidence: 99%

Strategies for the Diversity-Oriented Synthesis of Macrocycles

et al. 2019

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Macrocycles have long been recognized as useful chemical entities for medicine, with naturally occurring and synthetic macrocycles clinically approved for use as prescription drugs. Despite this promise, the synthesis of collections of macrocycles has been historically challenging due to difficulties in the formation of large rings. Diversity-Oriented Synthesis (DOS) emerged in the early 2000s as a powerful strategic solution to the construction of diverse molecular libraries. This review details the various strategies developed within the field of DOS for the synthesis of macrocycle libraries, utilizing modern synthetic methodology to deliver structurally diverse collections of macrocyclic molecules, and the exploration of their therapeutic potential.

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Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity

Cited by 18 publications

References 22 publications

The Synthesis of Macrocycles for Drug Discovery

The Synthesis of Macrocycles for Drug Discovery

Recent Advances in Macrocyclic Hsp90 Inhibitors

Strategies for the Diversity-Oriented Synthesis of Macrocycles

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