Dunna Nageswara Rao, Kandula Venkatesh, Girdhar Amandeep, Pudutha Amareshwari, Hussain Tajamul, Bandaru Srinivas, Nayarisseri Anuraj
School of Chemical and Biotechnology, SASTRA University, Thanjavur, India E-mail :
Asian Pac J Cancer Prev. 2015;16(16):7089-95. doi: 10.7314/apjcp.2015.16.16.7089.
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.
临床证据表明，与单独抑制激酶或血管生成相比，同时抑制激酶和血管生成在甲状腺髓样癌（MTC）治疗中提供了理想的治疗选择。虽然双重抑制剂治疗在MTC患者中已显示出良好的临床反应，但它也伴随着严重的副作用。一些抑制剂对血管生成或激酶活性均为活性剂。由于现有抑制剂的治疗窗口狭窄，本研究旨在鉴定分别靶向RET和VEGFR2的激酶和血管生成活性的高亲和力双重抑制剂。将凡德他尼、卡博替尼、莫特沙尼、PP121、RAF265和舒尼替尼等现有抑制剂用作查询母体化合物，通过基于Tanimoto的相似度搜索，以95%的阈值在PubChem数据库中鉴定结构相似的化合物。所有母体抑制剂及其各自的相似化合物均与RET和VEGFR2对接，以检索与这两种蛋白质具有高亲和力的化合物。AGN-PC-0CUK9P（PubCID：59320403），一种与PPI21相关的化合物，对RET和VEGFR2显示出几乎相等的亲和力，并且与其他筛选化合物不同，对任何一种受体都没有明显的偏好。此外，AGN-PC-0CUK9P除了显示出最佳的ADMET性质和药效团特征外，还与RET和VEGFR2表现出明显的相互作用以及优异的激酶活性。通过我们的计算机模拟研究，我们建议AGN-PC-0CUK9P作为一种高效的靶向RET和VEGFR2的双重抑制剂，应建议进行药效学和药代动力学研究，以改善MTC的治疗。
