TY - JOUR
T1 - Development of a specific and potent IGF2BP1 inhibitor
T2 - A promising therapeutic agent for IGF2BP1-expressing cancers
AU - Singh, Amandeep
AU - Singh, Vikash
AU - Wallis, Nadav
AU - Abis, Giancarlo
AU - Oberman, Froma
AU - Wood, Tyler
AU - Dhamdhere, Mayura
AU - Gershon, Tehila
AU - Ramos, Andres
AU - Yisraeli, Joel
AU - Spiegelman, Vladimir S.
AU - Sharma, Arun K.
N1 - Publisher Copyright:
© 2023 Elsevier Masson SAS
PY - 2024/1/5
Y1 - 2024/1/5
N2 - IGF2BP1 is a protein that controls the stability, localization, and translation of various mRNA targets. Poor clinical outcomes in numerous cancer types have been associated with its overexpression. As it has been demonstrated to impede tumor growth and metastasis in animal models, inhibiting IGF2BP1 function is a promising strategy for combating cancer. A lead chemical, 7773, which specifically decreased IGF2BP1 RNA binding and cellular activities, was previously identified in a high-throughput screen for effective IGF2BP1 inhibitors. Additional optimization of 7773 described in this manuscript led to the discovery of six compounds that performed equally well or better than 7773. In cell lines with high levels of endogenous IGF2BP1, one of 7773 derivatives, AVJ16, was found to be most efficient at preventing cell migration. Further, AVJ16 was found to be IGF2BP1-specific because it had no effect on cell lines that expressed little or no IGF2BP1 protein. The direct binding of AVJ16 to IGF2BP1 was validated by binding tests, with a 12-fold increase in binding efficiency over the lead compound. AVJ16 was shown to bind to a hydrophobic region at the protein's KH34 di-domain interface between the KH3 and KH4 domains. Overall, the findings imply that AVJ16 is a potent and specific inhibitor of IGF2BP1 activity.
AB - IGF2BP1 is a protein that controls the stability, localization, and translation of various mRNA targets. Poor clinical outcomes in numerous cancer types have been associated with its overexpression. As it has been demonstrated to impede tumor growth and metastasis in animal models, inhibiting IGF2BP1 function is a promising strategy for combating cancer. A lead chemical, 7773, which specifically decreased IGF2BP1 RNA binding and cellular activities, was previously identified in a high-throughput screen for effective IGF2BP1 inhibitors. Additional optimization of 7773 described in this manuscript led to the discovery of six compounds that performed equally well or better than 7773. In cell lines with high levels of endogenous IGF2BP1, one of 7773 derivatives, AVJ16, was found to be most efficient at preventing cell migration. Further, AVJ16 was found to be IGF2BP1-specific because it had no effect on cell lines that expressed little or no IGF2BP1 protein. The direct binding of AVJ16 to IGF2BP1 was validated by binding tests, with a 12-fold increase in binding efficiency over the lead compound. AVJ16 was shown to bind to a hydrophobic region at the protein's KH34 di-domain interface between the KH3 and KH4 domains. Overall, the findings imply that AVJ16 is a potent and specific inhibitor of IGF2BP1 activity.
UR - http://www.scopus.com/inward/record.url?scp=85178650152&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85178650152&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2023.115940
DO - 10.1016/j.ejmech.2023.115940
M3 - Article
C2 - 37976707
AN - SCOPUS:85178650152
SN - 0223-5234
VL - 263
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 115940
ER -