High Affinity Pharmacological Profiling of Dual Inhibitors Targeting RET and VEGFR2 in Inhibition of Kinase and Angiogeneis Events in Medullary Thyroid Carcinoma

Abstract

Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic optionin the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately.Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has beenassociated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity.Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinitydual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Establishedinhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parentcompounds for identification of structurally similar compounds by Tanimoto-based similarity searching with athreshold of 95% against the PubChem database. All the parent inhibitors and respective similar compoundswere docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins.AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET andVEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGNPC-0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity inaddition to showed optimal ADMET properties and pharmacophore features. From our in silico investigationwe suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy whichshould be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.