Small Molecule c-KIT Inhibitors for the Treatment of Gastrointestinal Stromal Tumors: A Review on Synthesis, Design Strategies, and Structure–Activity Relationship (SAR)

Sreenivasulu Godesi, Joohan Lee, Hossam Nada, Guofeng Quan, Ahmed Elkamhawy, Yongseok Choi, Kyeong Lee

Research output: Contribution to journalReview articlepeer-review

2 Citations (Scopus)

Abstract

The proto-oncogenic protein, c-KIT, plays a crucial role in regulating cellular transformation and differentiation processes, such as proliferation, survival, adhesion, and chemotaxis. The overexpression of, and mutations, in c-KIT can lead to its dysregulation and promote various human cancers, particularly gastrointestinal stromal tumors (GISTs); approximately 80–85% of cases are associated with oncogenic mutations in the KIT gene. Inhibition of c-KIT has emerged as a promising therapeutic target for GISTs. However, the currently approved drugs are associated with resistance and significant side effects, highlighting the urgent need to develop highly selective c-KIT inhibitors that are not affected by these mutations for GISTs. Herein, the recent research efforts in medicinal chemistry aimed at developing potent small-molecule c-KIT inhibitors with high kinase selectivity for GISTs are discussed from a structure–activity relationship perspective. Moreover, the synthetic pathways, pharmacokinetic properties, and binding patterns of the inhibitors are also discussed to facilitate future development of more potent and pharmacokinetically stable small-molecule c-KIT inhibitors.

Original languageEnglish
Article number9450
JournalInternational journal of molecular sciences
Volume24
Issue number11
DOIs
Publication statusPublished - 2023 Jun

Bibliographical note

Funding Information:
This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [No. 2018R1A5A2023127] & [No. 2023R1A2C3004599]. This work is also supported by the BK21 FOUR program, which was funded by the Ministry of Education of Korea through NRF.

Publisher Copyright:
© 2023 by the authors.

Keywords

  • c-KIT
  • c-KIT inhibitors
  • GISTs
  • SAR
  • SCFR
  • stem cell growth factor

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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