TY - JOUR
T1 - Small molecule inhibitor of Igf2bp1 represses Kras and a pro-oncogenic phenotype in cancer cells
AU - Wallis, Nadav
AU - Oberman, Froma
AU - Shurrush, Khriesto
AU - Germain, Nicolas
AU - Greenwald, Gila
AU - Gershon, Tehila
AU - Pearl, Talia
AU - Abis, Giancarlo
AU - Singh, Vikash
AU - Singh, Amandeep
AU - Sharma, Arun K.
AU - Barr, Haim M.
AU - Ramos, Andres
AU - Spiegelman, Vladimir S.
AU - Yisraeli, Joel K.
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2022
Y1 - 2022
N2 - Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).
AB - Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).
KW - Fluorescence polarization
KW - Igf2bps
KW - Kras inhibitor
KW - RNA binding proteins
UR - http://www.scopus.com/inward/record.url?scp=85121439556&partnerID=8YFLogxK
U2 - 10.1080/15476286.2021.2010983
DO - 10.1080/15476286.2021.2010983
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C2 - 34895045
AN - SCOPUS:85121439556
SN - 1547-6286
VL - 19
SP - 26
EP - 43
JO - RNA Biology
JF - RNA Biology
IS - 1
ER -
