Discovery of Potent and Orally Bioavailable Macrocyclic Peptide–Peptoid Hybrid CXCR7 Modulators

Boehm, Markus; Beaumont, Kevin; Jones, Rhys; Kalgutkar, Amit S.; Zhang, Liying; Atkinson, Karen; Bai, Guoyun; Brown, Janice A.; Eng, Heather; Goetz, Gilles H.; Holder, Brian; Khunte, Bhagyashree; Lazzaro, Sarah; Limberakis, Chris; Ryu, Sangwoo; Shapiro, Michael J.; Tylaska, Laurie; Yan, Jiangli; Turner, Rushia; Leung, Siegfried S. F.; Ramaseshan, Mahesh; Price, David A.; Liras, Spiros; Jacobson, Matthew P.; Earp, David J.; Lokey, R. Scott; Mathiowetz, Alan M.; Menhaji‐Klotz, Elnaz

doi:10.1021/acs.jmedchem.7b01028

Cited by 58 publications

(50 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although no specific name was offered, Boehm et al recently reported a macrocyclic peptide-peptoid hybrid molecule, which binds to CXCR7 with high affinity ( K i < 100 nM) and measurable passive permeability ( P app > 5 × 10 -6 cm/s). The bioactive peptide 25 ( K i = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration ( Boehm et al, 2017 ). In addition, FC313, a cyclic pentapeptide ligand for CXCR7, which is modified at the I-Pro position with a bulky hydrophobic side chain, exhibited an improved bioactivity toward CXCR7 ( Sekiguchi et al, 2018 ).…”

Section: Pharmacological Ligands Of Cxcr7supporting

confidence: 58%

CXCR7 Targeting and Its Major Disease Relevance

2018

View full text Add to dashboard Cite

Chemokine receptors are the target of small peptide chemokines. They play various important roles in physiological and pathological processes. CXCR7, later renamed ACKR3, is a non-classical seven transmembrane-spanning receptor whose function as a signaling or non-signaling scavenger/decoy receptor is currently under debate. Even for cell signaling mechanisms, there has been inconsistency on whether CXCR7 couples to G-proteins or β-arrestins. Several reasons may contribute to this uncertainty or controversy. In one hand, it has been neglected that CXCR7 has more than five natural ligands and unfortunately, most of the prior research only studied SDF-1 (CXCL12) and/or I-TAC (CXCL11); on the other hand, there are mounting evidence supporting ligand and tissue bias for receptor signaling, but limited such information is available for CXCR7. In this review we focus on summarizing the endogenous and exogenous ligands of CXCR7, the main diseases related to CXCR7 and the biased signaling events happening on CXCR7. These three aspects of CXCR7 pharmacologic properties may explain why the contradicting opinions of whether CXCR7 is a signaling or non-signaling receptor exist. Further, potential new direction and perspective for the study of CXCR7 biology and pharmacology are highlighted.

show abstract

Section: Pharmacological Ligands Of Cxcr7supporting

confidence: 58%

CXCR7 Targeting and Its Major Disease Relevance

2018

View full text Add to dashboard Cite

show abstract

“…FouchØ,e tal.,r ecently reported ah ighly membrane permeable cyclic decapeptide which showed that favorable ADME and PK properties can be achieved in synthetic cyclic peptides with molecular weights above 1000 Da (Figure 1a). [10] Since peptoids are derived from primary amines and can therefore extend the range of chemical functionality that can be incorporated into ac yclic peptide, [11] we initially set out to determine whether permeability could be maintained in this system upon substitution with peptoid residues. Serendipitously,w ef ound that peptoid substitutions in these macrocycles had as pecific effect on conformational flexibility,s uch that solvent-dependent chameleonicity could be tuned depending on the location of the peptoid substitutions within the scaffold.…”

Section: Introductionmentioning

confidence: 99%

Drug‐Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side‐Chain Lipophilicity

Furukawa

Schwochert²,

Pye³

et al. 2020

Angewandte Chemie

Self Cite

View full text Add to dashboard Cite

Large macrocyclic peptides can achieve surprisingly high membrane permeability,a lthough the properties that govern permeability in this chemical space are only beginning to come into focus.W eg enerated two libraries of cyclic decapeptides with stable cross-b conformations,and found that peptoid substitutions within the b-turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing b-strands led to "chameleonic" species that were rigid in nonpolar media but highly flexible in water.B oth rigid and chameleonic compounds showed high permeability over aw ide lipophilicity range,w ith peak permeabilities differing significantly depending on scaffold rigidity.Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides,and that scaffold rigidity can be used to tune optimal lipophilicity.

show abstract

“…Favorable permeability profiles were shown to be consistent and tolerant to variations in oligomer side chain type 65 . Recently, another hexameric peptoid-peptide macrocycle, designed as a CXCR7 modulator, was demonstrated to exhibit both membrane permeability and oral bioavailability in rats 66 . In addition to pharmacokinetic issues, there is the potential that targeting β-catenin will lead to on-target toxicity 67 .…”

Section: Discussionmentioning

confidence: 99%

Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer

et al. 2018

View full text Add to dashboard Cite

New chemical inhibitors of protein–protein interactions are needed to propel advances in molecular pharmacology. Peptoids are peptidomimetic oligomers with the capability to inhibit protein-protein interactions by mimicking protein secondary structure motifs. Here we report the in silico design of a macrocycle primarily composed of peptoid subunits that targets the β-catenin:TCF interaction. The β-catenin:TCF interaction plays a critical role in the Wnt signaling pathway which is over-activated in multiple cancers, including prostate cancer. Using the Rosetta suite of protein design algorithms, we evaluate how different macrocycle structures can bind a pocket on β-catenin that associates with TCF. The in silico designed macrocycles are screened in vitro using luciferase reporters to identify promising compounds. The most active macrocycle inhibits both Wnt and AR-signaling in prostate cancer cell lines, and markedly diminishes their proliferation. In vivo potential is demonstrated through a zebrafish model, in which Wnt signaling is potently inhibited.

show abstract

Discovery of Potent and Orally Bioavailable Macrocyclic Peptide–Peptoid Hybrid CXCR7 Modulators

Cited by 58 publications

References 51 publications

CXCR7 Targeting and Its Major Disease Relevance

CXCR7 Targeting and Its Major Disease Relevance

Drug‐Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side‐Chain Lipophilicity

Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer

Contact Info

Product

Resources

About