Establishment of a Mid-Sized Molecule Drug Discovery Platform and Development of the Oral KRAS Inhibitor LUNA18

DOI
  • Kojima Tetsuo
    Chugai Pharmaceutical Company Limited
  • Shiraishi Takuya
    Discovery Chemistry Department, Research Division, Chugai Pharmaceutical Company Limited
  • Ohta Atsushi
    Modality Technology Department, Research Division, Chugai Pharmaceutical Company Limited
  • Tanada Mikimasa
    Discovery Chemistry Department, Research Division, Chugai Pharmaceutical Company Limited
  • Nomura Kenichi
    Discovery Chemistry Department, Research Division, Chugai Pharmaceutical Company Limited

Bibliographic Information

Other Title
  • 中分子創薬プラットフォームの構築と経口KRAS阻害剤LUNA18の創製

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Description

<p>We have established a mid-sized molecule drug discovery platform aimed at continuous drug discovery for tough targets that are challenging with existing modalities such as antibodies and small molecules. Our concept focuses on creating clinical compounds through simple structural optimization, starting from hits that combine pharmacological activity and drug-likeness. We selected cyclic peptides with a molecular weight of around 1500 as the drug discovery modality. After establishing a parallel synthesis method for peptides rich in N-alkyl amino acids, we defined structural requirements for cyclic peptides that can possess both metabolic stability and membrane permeability. Furthermore, we constructed an mRNA display capable of presenting these drug-like peptides and obtained the hit compound AP8784 against KRAS, an intracellular tough target. The clinical compound LUNA18, derived from the structural optimization of AP8784, maintains the active structure of the hit compound, demonstrating the validity of our drug discovery concept.</p>

Journal

  • MEDCHEM NEWS

    MEDCHEM NEWS 35 (2), 87-92, 2025-05-01

    The Pharmaceutical Society of Japan

Keywords

Details 詳細情報について

  • CRID
    1390585504098335872
  • DOI
    10.14894/medchem.35.2_87
  • ISSN
    24328626
    24328618
  • Text Lang
    ja
  • Data Source
    • JaLC
  • Abstract License Flag
    Disallowed

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