TMC‐95A Analogues with Endocyclic Biphenyl Ether Group as Proteasome Inhibitors

Kaiser, Markus; Milbradt, Alexander G.; Siciliano, Carlo; Assfalg-Machleidt, Irmgard; Machleidt, Werner; Groll, M.; Renner, Christian; Moröder, Luis

doi:10.1002/cbdv.200490008

Cited by 46 publications

(37 citation statements)

References 52 publications

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“…Compared to the previously reported noncovalent macrocyclic peptide BIA-1a (Figure 1), the covalently binding macrocyclic aldehydes reported here are 1000-fold more potent. 17,23 In addition to being the first macrocyclic peptide aldehydes with specificity for the proteasome, we found that introduction of a macrocycle significantly increases selectivity for the proteasome over intracellular cysteine proteases, such as calpains and cathepsins.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 90%

“…22 In accordance with previously synthesized biaryl ether analogues of TMC-95A, a modified Phe at P 4 and Tyr at P 2 were used to generate the ether macrocycle. 23 Leu was selected for the P 1 position based on the peptide sequence of carfilzomib and MG-132 and is thought to form favorable interactions with Met45 in the S 1 pocket of the β5 subunit. 24 The P 3 position was varied between two hydrophobic residues, Leu and Phe(OMe).…”

mentioning

confidence: 99%

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Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome

Wilson

Meininger

Strater

et al. 2016

ACS Med. Chem. Lett.

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This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors of the 20S proteasome. Two novel macrocyclic peptide aldehydes based on the ring-size of the macrocyclic natural product TMC-95 were prepared and evaluated as inhibitors of the 20S proteasome. Both compounds inhibited in the low nanomolar range and proved to be selective for the proteasome over other serine and cysteine proteases, particularly when compared to linear analogues with similar amino acid sequences. In HeLa cells, both macrocycles efficiently inhibited activation of nuclear factor-κB (NF-κB) transcription factor by blocking proteasomal degradation of the inhibitor protein IκBα after cytokine stimulation. Due to their covalent mechanism of binding these compounds represent a 1000-fold increase in inhibitory potency over previously reported noncovalently binding TMC-95 analogues. Molecular modeling of the macrocyclic peptides confirms the preference of the large S 3 pocket for large, hydrophobic residues and the ability to exploit this to improve selectivity of proteasome inhibitors.

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 90%

mentioning

confidence: 99%

Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome

Wilson

Meininger

Strater

et al. 2016

ACS Med. Chem. Lett.

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“…3a) [41]. In these compounds, a biphenyl ether clamp has been used to preorganize the peptide backbone into an extended -sheet conformation.…”

Section: Biphenyl Ethersmentioning

confidence: 99%

Macrocyclic Proteasome Inhibitors

Krahn¹,

Ottmann²,

Kaiser³

2011

CMC

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Proteasome inhibitors have proven to be effective anticancer agents. Despite the success of the first on the market proteasome inhibitor bortezomib in chemotherapy, alternative clinically useful proteasome inhibitors are still urgently needed as bortezomib therapy causes severe side effects and is limited by arising drug resistance. Experience from previous proteasome inhibitor studies has thereby demonstrated that the identification of proteasome inhibitor structures with suitable pharmacological properties is a key factor for a successful development of clinically useful proteasome inhibitors. Macrocycles often show distinct and in comparison to linear small molecules superior pharmacological properties. Consequently, macrocyclic proteasome inhibitors might represent promising small molecules for drug development. Here, we want to highlight the current state of the art of macrocyclic proteasome inhibitor research. To this end, we give an overview and critically discuss currently known classes of macrocyclic proteasome inhibitors.

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“…Another key structural modification was disclosed by the Moroder group in 2004 [22]. Considering that the role of the phenoleoxindole biaryl system in TMC-95 is to induce and stabilize an extended b-type peptide backbone conformation, which is mandatory for optimal interaction with the proteasome, they planned to replace this complex framework by an endocyclic biaryl ether.…”

Section: Moroder's Tmc-95a Analoguesmentioning

confidence: 99%