Gab2 is a scaffolding protein that plays a key role in cellular proliferation, migration ad differentiation. Indeed, it is overexpressed in many types of cancer’s tissues as breast gastric, lung, and colorectal. The interaction between Gab2 and the C-terminal SH3 domain of Gbr2 represents one of the first steps of activation of the Ras/Erk, an important proliferation-signaling pathway, thus being a valuable potential anticancer drug target. Therefore, a virtual screening study allowed us to identify seven potential inhibitor molecules, that were tested through kinetic and equilibrium binding experiments. From the results obtained, the only compound that showed inhibitory activity against the above interaction is AN-465-J137-985.1 Molecular docking studies on Gbr’s SH3-domain of this derivative provided insights into the molecular determinants responsible for its high affinity toward the target. The superimposition of the AN-465-J137-985 proposed binding and Gab2 core highlighted that three aromatic rings were superimposable with Pro512 and Val513 side chains, besides the Arg515 backbone is similar to hydrophobic contact observed for the substrate (Figure 1). To further investigate the effect of AN-465-J137-985 we treated A549 and H1299, lung cancer cell lines, with increasing doses of AN-465-J137-985, evaluating the potential anti-cancer effects of this molecule. The compound was shown to significantly inhibit the growth of both cancer cell lines. In particular, it exhibits values of lethal dose 50 (LD50) of about 5 and 7 µM for H1299 and A549, respectively. In this context, our studies will be aimed at the synthesis of new Gab 2 inhibitors starting from lead compound AN-465-J137-985. We will try to improve pharmacokinetic properties by trying to alternately insert groups of various groups of various kinds on the aromatic rings. References 1. Malagrinò, F. et al. Targeting the Interaction between the SH3 Domain of Grb2 and Gab2. Cells, 2020, 9, e2435.
A new potential target in oncological therapy: the interaction between Gab2 with SH3-domain of GBR2 / Sebastiani, J.; Coluccia, A.; La Regina, G.; Gianni, S.; Silvestri, R.. - (2021). (Intervento presentato al convegno 13th Young Medicinal Chemist Symposium (Nuove Prospettive in Chimica Farmaceutica, NPCF13) tenutosi a Online meeting).
A new potential target in oncological therapy: the interaction between Gab2 with SH3-domain of GBR2
Sebastiani, J.;Coluccia, A.;La Regina, G.;Gianni, S.;Silvestri, R.
2021
Abstract
Gab2 is a scaffolding protein that plays a key role in cellular proliferation, migration ad differentiation. Indeed, it is overexpressed in many types of cancer’s tissues as breast gastric, lung, and colorectal. The interaction between Gab2 and the C-terminal SH3 domain of Gbr2 represents one of the first steps of activation of the Ras/Erk, an important proliferation-signaling pathway, thus being a valuable potential anticancer drug target. Therefore, a virtual screening study allowed us to identify seven potential inhibitor molecules, that were tested through kinetic and equilibrium binding experiments. From the results obtained, the only compound that showed inhibitory activity against the above interaction is AN-465-J137-985.1 Molecular docking studies on Gbr’s SH3-domain of this derivative provided insights into the molecular determinants responsible for its high affinity toward the target. The superimposition of the AN-465-J137-985 proposed binding and Gab2 core highlighted that three aromatic rings were superimposable with Pro512 and Val513 side chains, besides the Arg515 backbone is similar to hydrophobic contact observed for the substrate (Figure 1). To further investigate the effect of AN-465-J137-985 we treated A549 and H1299, lung cancer cell lines, with increasing doses of AN-465-J137-985, evaluating the potential anti-cancer effects of this molecule. The compound was shown to significantly inhibit the growth of both cancer cell lines. In particular, it exhibits values of lethal dose 50 (LD50) of about 5 and 7 µM for H1299 and A549, respectively. In this context, our studies will be aimed at the synthesis of new Gab 2 inhibitors starting from lead compound AN-465-J137-985. We will try to improve pharmacokinetic properties by trying to alternately insert groups of various groups of various kinds on the aromatic rings. References 1. Malagrinò, F. et al. Targeting the Interaction between the SH3 Domain of Grb2 and Gab2. Cells, 2020, 9, e2435.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
