Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity

Zapf, Christoph W.; Bloom, Jonathan D.; McBean, Jamie L.; Dushin, Russell G.; Nittoli, Thomas; Ingalls, Charles L.; Sutherland, A.; Sonye, John P.; Eid, Clark N.; Golas, Jennifer M.; Líu, Hao; Boschelli, Frank; Hu, Yongbo; Vogan, Erik; Levin, Jeremy I.

doi:10.1016/j.bmcl.2011.02.101

Cited by 23 publications

(12 citation statements)

References 26 publications

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“…16 In addition, a rigidifying element, in the form of methyl substituents on the linker, was found to be beneficial for binding affinity and cellular activity. Thus, compound 31 (Figure 2.14), a 12-membered macrocycle with a basic amine in the linker and no additional substitution on the linking chain has an IC 50 of 920 nM in an Hsp90 enzyme inhibition assay.…”

Section: Class Iii: Macrocyclic O-aminobenzamides and Aminopyrimidinesmentioning

confidence: 99%

“…128 Among that group, two that have generated significant interest are the o-aminobenzamide SNX-2112 (28), [20][21][22] its pro-drug SNX-5422 (29, PF-04929113), 129 The transformation of SNX-2112 (28) into a potent macrocyclic Hsp90 inhibitor with acceptable drug-like properties and potent in vivo activity began with an analysis of its key binding interactions to the protein, direct and water-mediated hydrogen bonds between the benzamide -NH 2 group and Asp93 and a hydrogen bond between the carbonyl of the tetrahydroindazole of 28 and Tyr139 of the ATPase. 16 The requirement that both of these interactions be maintained for high affinity binding to the protein then defined a range of acceptable torsion angles between the benzamide and tetrahydroindolone ring, which further defined the size of the linker that could be accommodated connecting the two rings in a macrocycle (Figure 2.14). The physical properties of the linker, for example its polarity, were not expected to have a significant effect on potency given that it would be solvent exposed.…”

Section: Class Iii: Macrocyclic O-aminobenzamides and Aminopyrimidinesmentioning

confidence: 99%

“…13 Synthetic derivatives of geldanamycin continue to dominate clinical research, but new macrocycles based on other types of scaffolds have demonstrated preclinical promise and expanded the structures of N-terminal binding molecules. [14][15][16] Although the efficacy of the potent Class II inhibitor radicicol is diminished in vivo due to its metabolic instability, improvements incorporated into its synthetic derivatives and chimeras such as radanamycin have led to greater structural stability without loss of potency. [17][18][19] Class III inhibitors include the o-aminobenzamide SNX-2112 and the purineclass inhibitor BIIB021, which have been evaluated in several completed clinical trials.…”

Section: Macrocycles As Anticancer Agentsmentioning

confidence: 99%

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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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Section: Class Iii: Macrocyclic O-aminobenzamides and Aminopyrimidinesmentioning

confidence: 99%

Section: Class Iii: Macrocyclic O-aminobenzamides and Aminopyrimidinesmentioning

confidence: 99%

Section: Macrocycles As Anticancer Agentsmentioning

confidence: 99%

See 1 more Smart Citation

Recent Advances in Macrocyclic Hsp90 Inhibitors

Ramsey

Kitson

Levin

et al. 2014

Macrocycles in Drug Discovery

View full text Add to dashboard Cite

show abstract

“…Table 10.1 demonstrates the impact of the linker on the CYP P450 metabolism, as measured in rat liver microsomes, for a series of Hsp90 inhibitors. 17 In addition, for the case of peptides, cyclization can eliminate systemic proteolytic degradation, thereby decreasing F h for cyclic peptides. 18 A study of the acyclic decapeptide H-LLEDPVGTVA-NH2 compared to cyclic peptide, disulfide, and thioether variations 18 showed that the acyclic peptide had completely disappeared in 10% human serum after 24 hours, while the cyclic variants were still at least 90% intact.…”

Section: Pharmacokinetic Benefits Of Macrocyclizationmentioning

confidence: 99%

Optimizing the Permeability and Oral Bioavailability of Macrocycles

Mathiowetz

Leung²,

Jacobson

2014

Macrocycles in Drug Discovery

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Macrocycles have a number of inherent advantages that improve their prospects for achieving oral bioavailability, even when their physical properties lie outside the traditional Rule-of-5 chemistry space. This chapter provides an overview of these advantages, with particular attention given to the potential for macrocycles to adopt three-dimensional conformations that overcome barriers to permeability. An overview of the relationship between physical properties and oral bioavailability is given along with a more detail description of permeability, including recent developments in using fundamental physics to predict passive permeability. A variety of orally bioavailable macrocycles is described, including both natural products and compounds discovered through medicinal chemistry. In addition, some structure property relationships are described, which were identified during the process of optimizing these macrocycles.

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“…1,2 Among the various classes of nitrogen-containing heterocycles, indoles have many biological and pharmacological activities, such as GABA receptor ligands, 3 antipsychotic, 4 anticancer, 5 antioxidant, 6 antiproliferative agents, 7 antirheumatoidal and anti-HIV, 8,9 and as soluble guanylatecyclase inhibitors. 10,11 Therefore, the synthesis and selective functionalization of indoles 12-14 and using indoles as starting materials for the synthesis of a series of alkaloids, pharmaceuticals and perfumes 15 have been the focus of researchers. A number of these are costly and harmful to the environment.…”

Section: Introductionmentioning

confidence: 99%