TY - JOUR
T1 - Discovery and optimization of natural-based nanomolar c-Kit inhibitors via in silico and in vitro studies
AU - Nada, Hossam
AU - Kim, Sungdo
AU - Godesi, Sreenivasulu
AU - Lee, Joohan
AU - Lee, Kyeong
N1 - Publisher Copyright:
© 2023 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2023
Y1 - 2023
N2 - c-Kit is a receptor tyrosine kinase which is involved in intracellular signaling and mutations of c-Kit have been associated with various types of cancers. Investigations have shown that inhibition of c-Kit, using tyrosine kinase inhibitors, yielded promising results in cancer treatment marking it as a promising target for cancer therapy. However, the emerging resistance for the current therapy necessitates the development of more potent inhibitors which are not affected by these mutations. Herein, virtual screening of a library of natural-based compounds yielded three hits (2, 5 and 6) which possessed nanomolar inhibitory (2.02, 4.33 and 2.80 nM, respectively) activity when tested in vitro against c-Kit. Single point mutation docking studies showed the hits to be unaffected by the most common resistance mutation in imatinib-resistant cells, mutation of Val654. Although, the top hits exhibited around 3000 higher inhibitory potency toward c-Kit when compared to imatinib (5.4 µM), previous studies have shown that they are metabolically unstable. Fragment-based drug design approaches were then employed to enhance binding affinity of the top hit and make it more metabolically stable. Screening of the generated fragments yielded a new derivative, F1, which demonstrated stronger binding affinity, stability and binding free energy when compared to the hit compound 2. Communicated by Ramaswamy H. Sarma.
AB - c-Kit is a receptor tyrosine kinase which is involved in intracellular signaling and mutations of c-Kit have been associated with various types of cancers. Investigations have shown that inhibition of c-Kit, using tyrosine kinase inhibitors, yielded promising results in cancer treatment marking it as a promising target for cancer therapy. However, the emerging resistance for the current therapy necessitates the development of more potent inhibitors which are not affected by these mutations. Herein, virtual screening of a library of natural-based compounds yielded three hits (2, 5 and 6) which possessed nanomolar inhibitory (2.02, 4.33 and 2.80 nM, respectively) activity when tested in vitro against c-Kit. Single point mutation docking studies showed the hits to be unaffected by the most common resistance mutation in imatinib-resistant cells, mutation of Val654. Although, the top hits exhibited around 3000 higher inhibitory potency toward c-Kit when compared to imatinib (5.4 µM), previous studies have shown that they are metabolically unstable. Fragment-based drug design approaches were then employed to enhance binding affinity of the top hit and make it more metabolically stable. Screening of the generated fragments yielded a new derivative, F1, which demonstrated stronger binding affinity, stability and binding free energy when compared to the hit compound 2. Communicated by Ramaswamy H. Sarma.
KW - c-kit inhibitors
KW - Fragment-based drug design
KW - Free energy calculations
KW - Molecular dynamics
KW - Virtual screening
UR - http://www.scopus.com/inward/record.url?scp=85146749949&partnerID=8YFLogxK
U2 - 10.1080/07391102.2022.2164061
DO - 10.1080/07391102.2022.2164061
M3 - Article
C2 - 36636795
AN - SCOPUS:85146749949
SN - 0739-1102
VL - 41
SP - 11904
EP - 11915
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 21
ER -