TY - JOUR
T1 - Small Molecule c-KIT Inhibitors for the Treatment of Gastrointestinal Stromal Tumors
T2 - A Review on Synthesis, Design Strategies, and Structure–Activity Relationship (SAR)
AU - Godesi, Sreenivasulu
AU - Lee, Joohan
AU - Nada, Hossam
AU - Quan, Guofeng
AU - Elkamhawy, Ahmed
AU - Choi, Yongseok
AU - Lee, Kyeong
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - c-KIT
KW - c-KIT inhibitors
KW - GISTs
KW - SAR
KW - SCFR
KW - stem cell growth factor
UR - http://www.scopus.com/inward/record.url?scp=85161511077&partnerID=8YFLogxK
U2 - 10.3390/ijms24119450
DO - 10.3390/ijms24119450
M3 - Review article
C2 - 37298401
AN - SCOPUS:85161511077
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 11
M1 - 9450
ER -