ChemInform Abstract: Dopamine D3 and D4 Receptor Antagonists: Synthesis and Structure‐ Activity Relationships of (S)‐(+)‐N‐(1‐Benzyl‐3‐pyrrolidinyl)‐5‐chloro‐ 4‐((cyclopropylcarbonyl)amino)‐2‐methoxybenzamide (YM‐43611) and Related Compounds.

Ohmori, Junya; Maeno, Kyoichi; Hidaka, Kazuyuki; Nakato, Kazuhiro; Matsumoto, Mitsuyuki; Tada, Shoko; Hattori, H.; Sakamoto, Satoshi; Tsukamoto, Shin‐ichi; Usuda, Shinji; Mase, Toshiaki

doi:10.1002/chin.199643082

Cited by 1 publication

(2 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…36−38 Furthermore, the attachment of bulky halogen atoms can increase binding contacts 39−41 and also enhance membrane permeability. 42 Ohmori et al 43 and Hidaka et al 44 showed that halogen modifications in the compound Nemonapride can be used to overcome low selectivity over D4 receptors and that removal of chlorine was deleterious for dopaminergic receptors selectivity. All of these data are supportive of the proposition that the aromatic halogenation of CR1166 results in a stronger binding interaction with the GIPC PDZ domain.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…, flavopiridol, a kinase inhibitor currently undergoing clinical trials, possesses a halogenated-phenyl group instead of unsubstituted phenyl, which increases its inhibitory effect by 6-fold. − Organic halogen atoms contribute to a variety of noncovalent protein–ligand interactions such as halogen bonds, hydrogen bonds, and electrostatic-type interactions that enhance the stability of ligand–target complexes. − Furthermore, the attachment of bulky halogen atoms can increase binding contacts − and also enhance membrane permeability . Ohmori et al and Hidaka et al showed that halogen modifications in the compound Nemonapride can be used to overcome low selectivity over D4 receptors and that removal of chlorine was deleterious for dopaminergic receptors selectivity. All of these data are supportive of the proposition that the aromatic halogenation of CR1166 results in a stronger binding interaction with the GIPC PDZ domain.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

et al. 2012

View full text Add to dashboard Cite

GIPC (GAIP-interacting protein, C terminus) represents a new target class for the discovery of chemotherapeutics. While many of the current generation of anticancer agents function by directly binding to intracellular kinases or cell surface receptors, the disruption of cytosolic protein-protein interactions mediated by non-enzymatic domains is an underdeveloped avenue for inhibiting cancer growth. One such example is the PDZ domain of GIPC. Previously we developed a molecular probe, the cell permeable octapeptide CR1023 (N-myristoyl-PSQSSSEA), which diminished proliferation of pancreatic cancer cells. We have expanded upon that discovery using a chemical modification approach, and here report a series of cell permeable, side chain-modified lipopeptides that target the GIPC PDZ domain in vitro and in vivo. These peptides exhibit significant activity against pancreatic and breast cancers, both in vitro and in animal models. CR1166 (N-myristoyl-PSQSK(εN-4-bromobenzoyl)SK(εN-4-bromobenzoyl)A), bearing two halogenated aromatic units on alternate side chains, was found to be the most active compound, with pronounced down-regulation of EGFR/1GF-1R expression. We hypothesize that these organic acid-modified residues extend the productive reach of the peptide beyond the canonical binding pocket, which defines the limit of accessibility for the native proteinogenic sequences that the PDZ domain has evolved to recognize. Cell permeability is achieved with N-terminal lipidation using myristate, rather than a larger CPP (cell-penetrating peptide) sequence. This, in conjunction with optimization of targeting through side chain modification, has yielded an approach that will allow the discovery and development of next-generation cellular probes for GIPC PDZ as well as other PDZ domains.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%