Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.
J Am Chem Soc
; 145(44): 24035-24051, 2023 11 08.
Article
in En
| MEDLINE
| ID: mdl-37874670
ABSTRACT
Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N-alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptides, Cyclic
Language:
En
Journal:
J Am Chem Soc
Year:
2023
Type:
Article
Affiliation country:
Japan