Current Trends in Macrocyclic Drug Discovery and beyond -Ro5

Alihodžić, Sulejman; Bukvić, Mirjana; Elenkov, Ivaylo; Hutinec, Antun; Koštrun, Sanja; Pešić, Dijana; Saxty, Gordon; Tomašković, Linda; Žiher, Dinko

doi:10.1016/bs.pmch.2018.01.002

Cited by 22 publications

(20 citation statements)

References 360 publications

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“…Macrocycles demonstrate drug-like physicochemical properties with respect to factors such as solubility and lipophilicity. They display oral bioavailability, metabolic stability and good pharmacokinetic and pharmacodynamic properties (Driggers et al 2008;Alihodzić et al 2018). However, macrocyclic natural products have not received much attention in addressing challenging PPI targets and in solving such pressing problems as the need for new drugs to combat microbial antibiotic resistance (Alihodzić et al 2018).…”

Section: Strategies For Targeting Protein-protein Interactionsmentioning

confidence: 99%

“…They display oral bioavailability, metabolic stability and good pharmacokinetic and pharmacodynamic properties (Driggers et al 2008;Alihodzić et al 2018). However, macrocyclic natural products have not received much attention in addressing challenging PPI targets and in solving such pressing problems as the need for new drugs to combat microbial antibiotic resistance (Alihodzić et al 2018). The emergence of strategies for the synthesis of macrocycle-rich chemical libraries such as B/C/P and the recent breakthrough in respect of the synthesis of organic compounds, such as olefin metathesis, have put macrocycles within easier reach of medicinal chemists (Lee and Grubbs 2001;Yu et al 2011).…”

Section: Strategies For Targeting Protein-protein Interactionsmentioning

confidence: 99%

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Protein-protein interaction modulators: advances, successes and remaining challenges

2019

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Modulating disease-relevant protein-protein interactions (PPIs) using small-molecule inhibitors is a quite indispensable diagnostic and therapeutic strategy in averting pathophysiological cues and disease progression. Over the years, targeting intracellular PPIs as drug design targets has been a challenging task owing to their highly dynamic and expansive interfacial areas (flat, featureless and relatively large). However, advances in PPI-focused drug discovery technology have been reported and a few drugs are already on the market, with some potential drug-like candidates already in clinical trials. In this article, we review the advances, successes and remaining challenges in the application of small molecules as valuable PPI modulators in disease diagnosis and therapeutics.

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Section: Strategies For Targeting Protein-protein Interactionsmentioning

confidence: 99%

Section: Strategies For Targeting Protein-protein Interactionsmentioning

confidence: 99%

Protein-protein interaction modulators: advances, successes and remaining challenges

2019

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“…[21,22] As such, macrocycles provide privileged scaffolds to target PPIs and protein surfaces,a mongst other challenging targets. [23][24][25] For example,t he archetypal macrolide natural products cyclosporine and rapamycin are macrocyclic molecules that act as molecular glues to induce the formation of at ernary complex. [26,27] To our knowledge,h owever, the use of macrocylization as as trategy for PROTACd esign, or more generally to bias recruitment of proteins together,r emains unprecedented.…”

Section: Introductionmentioning

confidence: 99%

“…Macrocyclization is expected to reduce the energetic penalty to adopt the bound state through conformational restriction . As such, macrocycles provide privileged scaffolds to target PPIs and protein surfaces, amongst other challenging targets . For example, the archetypal macrolide natural products cyclosporine and rapamycin are macrocyclic molecules that act as molecular glues to induce the formation of a ternary complex .…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Design of a Macrocyclic PROTAC

et al. 2019

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Constraining am olecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes.W hile this approach has been applied to enzyme inhibitors or receptor antagonists,t od ate it remains unprecedented for bifunctional molecules that bring proteins together,s uch as PROTAC degraders.H erein, we report the design and synthesis of am acrocyclic PROTACb ya dding ac yclizing linker to the BET degrader MZ1. Aco-crystal structure of macroPROTAC-1b ound in at ernary complex with VHL and the second bromodomain of Brd4 validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins.D espite a1 2-fold loss of binary binding affinity for Brd4, macro-PROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTACd egradation potency and selectivity between homologous targets.

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“…[21,22] As such, macrocycles provide privileged scaffolds to target PPIs and protein surfaces, amongst other challenging targets. [23][24][25] For example, the archetypal macrolide natural products cyclosporine and rapamycin are macrocyclic molecules that act as molecular glues to induce the formation of a ternary complex. [26,27] To our knowledge, however, the use of macrocylization as a strategy for PROTAC design, or more generally to bias recruitment of proteins together, remains unprecedented.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design of a Macrocyclic PROTAC

Testa¹,

Hughes²,

Lucas³

et al. 2019

Preprint

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Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to design enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC based on co-crystal structure of a parent linear molecule, by adding a cyclizing linker. A co-crystal structure of the macrocyclic PROTAC bound in a ternary complex with VHL and Brd4 validated the rational design and identified new interactions formed by the new linker. Biophysical studies revealed that the macrocycle selectively discriminated the second against the first bromodomains of BET proteins, and is a potent Brd4 degrader. Macrocyclization provides a viable strategy to induce protein-protein complexes and protein degradation inside cells.

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Current Trends in Macrocyclic Drug Discovery and beyond -Ro5

Cited by 22 publications

References 360 publications

Protein-protein interaction modulators: advances, successes and remaining challenges

Protein-protein interaction modulators: advances, successes and remaining challenges

Structure‐Based Design of a Macrocyclic PROTAC

Structure-Based Design of a Macrocyclic PROTAC

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