Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor

Cyclicpeptides as a therapeutic modality are attractinga lotof attention due to their potential for oral absorption and accessibilityto intracellular tough targets. Here, starting with a drug-like hitdiscovered using an mRNA display library, we describe a chemical optimizationthat led to the orally...

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Vydáno v:Journal of the American Chemical Society Ročník 145; číslo 30; s. 16610 - 16620
Hlavní autoři: Tanada, Mikimasa, Tamiya, Minoru, Matsuo, Atsushi, Chiyoda, Aya, Takano, Koji, Ito, Toshiya, Irie, Machiko, Kotake, Tomoya, Takeyama, Ryuuichi, Kawada, Hatsuo, Hayashi, Ryuji, Ishikawa, Shiho, Nomura, Kenichi, Furuichi, Noriyuki, Morita, Yuya, Kage, Mirai, Hashimoto, Satoshi, Nii, Keiji, Sase, Hitoshi, Ohara, Kazuhiro, Ohta, Atsushi, Kuramoto, Shino, Nishimura, Yoshikazu, Iikura, Hitoshi, Shiraishi, Takuya
Médium: Journal Article
Jazyk:angličtina
Vydáno: WASHINGTON Amer Chemical Soc 02.08.2023
Témata:
Chemistry
Chemistry, Multidisciplinary
Physical Sciences
Science & Technology
CHAIN
PERMEABILITY
SMALL-MOLECULE INHIBITORS
DRUG DISCOVERY
MESSENGER-RNA DISPLAY
BINDING
CYCLOSPORINE
INSIGHTS
ISSN:0002-7863, 1520-5126, 1520-5126
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Shrnutí:Cyclicpeptides as a therapeutic modality are attractinga lotof attention due to their potential for oral absorption and accessibilityto intracellular tough targets. Here, starting with a drug-like hitdiscovered using an mRNA display library, we describe a chemical optimizationthat led to the orally available clinical compound known as LUNA18,an 11-mer cyclic peptide inhibitor for the intracellular tough targetRAS. The key findings are as follows: (i) two peptide side chainswere identified that each increase RAS affinity over 10-fold; (ii)physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increasemembrane permeability; (iii) restriction of cyclic peptide conformationworks effectively to adjust PCP and improve bio-activity; (iv) cellularefficacy was observed in peptides with a permeability of around 0.4x 10(-6) cm/s or more in a Caco-2 permeabilityassay; and (v) while keeping the cyclic peptide's main-chainconformation, we found one example where the RAS protein structurewas changed dramatically through induced-fit to our peptide side chain.This study demonstrates how the chemical optimization of bio-activepeptides can be achieved without scaffold hopping, much like the processesfor small molecule drug discovery that are guided by Lipinski'srule of five. Our approach provides a versatile new strategy for generatingpeptide drugs starting from drug-like hits.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.3c03886