title: 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 option in 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 been associated 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 affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were 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 and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGN- PC-0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.
authors.affiliation: School of Chemical and Biotechnology, SASTRA University, Thanjavur, India E-mail : anuraj@eminentbio.com.
authors.forename: Nageswara Rao
authors.initials: NR
authors.lastname: Dunna
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Kandula
authors.forename: Amandeep
authors.initials: A
authors.lastname: Girdhar
authors.forename: Amareshwari
authors.initials: A
authors.lastname: Pudutha
authors.forename: Tajamul
authors.initials: T
authors.lastname: Hussain
authors.forename: Srinivas
authors.initials: S
authors.lastname: Bandaru
authors.forename: Anuraj
authors.initials: A
authors.lastname: Nayarisseri
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000813:Anilides / Q000737:chemistry; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy*; D062126:Databases, Chemical; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry; D009841:Oligonucleotides; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D011799:Quinazolines / Q000737:chemistry; D000077210:Sunitinib; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D000813:Anilides; D007093:Imidazoles; D007211:Indoles; D009841:Oligonucleotides; C533409:PP121 compound; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D011799:Quinazolines; C558660:cabozantinib; D009536:Niacinamide; C559019:RAF265; C000588866:KDR protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; C519562:imetelstat; D000077210:Sunitinib; C452423:vandetanib