La Monica Gabriele, Pizzolanti Giuseppe, Baiamonte Concetta, Bono Alessia, Alamia Federica, Mingoia Francesco, Lauria Antonino, Martorana Annamaria
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, University of Palermo, viale delle Scienze, Ed.17, 90128 Palermo, Italy.
ACS Omega. 2023 Sep 11;8(38):34640-34649. doi: 10.1021/acsomega.3c03578. eCollection 2023 Sep 26.
RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. Herein, we performed an innovative ligand-based virtual screening protocol using the DRUDIT web service, focusing on the RET kinase as a biological target. In this process, thieno[3,2-]quinolines and were proposed as new potential RET inhibitors. The selected compounds were synthetized by appropriate synthetic strategies, and evaluation of antiproliferative properties conducted on the particularly aggressive MTC cell line TT(C634R) identified compounds as promising anticancer agents, with IC values in the micromolar range. Further structure-based computational studies revealed a significant capability of the most active compounds to the complex RET tyrosine kinase domain. The interesting antiproliferative results supported by predictions suggest that these compounds may represent a starting point for the development of a new series of small heterocyclic molecules for the treatment of MTC.
RET激酶功能获得性突变是甲状腺髓样癌（MTC）高侵袭性和转移性的主要原因。选择性抑制RET激酶是治疗这种内分泌肿瘤的合适策略。在此，我们使用DRUDIT网络服务执行了一种创新的基于配体的虚拟筛选方案，将RET激酶作为生物学靶点。在此过程中，噻吩并[3,2 - ]喹啉被提出作为新的潜在RET抑制剂。通过适当的合成策略合成了所选化合物，并对特别具有侵袭性的MTC细胞系TT（C634R）进行了抗增殖特性评估，确定这些化合物为有前景的抗癌剂，其IC值在微摩尔范围内。进一步基于结构的计算研究表明，活性最高的化合物与RET酪氨酸激酶结构域具有显著的结合能力。预测支持的有趣抗增殖结果表明，这些化合物可能代表开发用于治疗MTC的新系列小杂环分子的起点。
