Design and Development of Novel Hybrids Based on Pyrrolo[2,1-f][1,2,4]Triazine and 1-(Methylpiperidin-4-yl) Aniline–Based Analogs: Exploring the Utility as Anticancer Agents via MERTK Inhibition

IF 3.2 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Balaji Dashrath Sathe, Shivani Jaiswal, Devendra Kumar, Thakur Gurjeet Singh, Nidhi Nainwal, Pramod Rawat, Savita Yadav, Bhupinder Kumar, Ashish Ranjan Dwivedi, S. V. Rathod
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Abstract

Mer-tyrosine kinase (MERTK), a member of the AXL, TYRO3, and MERTK (TAM) family, is one of the promising targets for cancer treatment. It plays a key role in cancer cell survival and proliferation and regulates immune responses in cancer. The study aimed to rationally design and develop molecules considering the pharmacophoric requirements of MERTK using a multi-synthetic approach followed by the hybridization of individual pharmacophores. A hybrid drug design approach was employed by hybridization of pyrrolo[2,1-f][1,2,4]triazine and 1-(methylpiperidin-4-yl)aniline pharmacophoric systems to develop novel leads (1K1–1K5). The molecules were synthesized via a multi-step synthetic approach. The synthesized molecules were assessed for their pharmacological potential via cell viability, drug metabolism and pharmacokinetics (DMPK), and MERTK inhibition studies corroborated by in silico studies. IK5 was found to have an IC50 value of 0.36 μM towards A549, followed by 0.42 μM and 0.80 μM against MCF-7 and MDA-MB-231 cells, respectively. Further, the molecules were also analyzed for their microsomal stability and were found to be stable with better intrinsic clearance profiles. The molecules thus pave a strategy for developing novel MERTK inhibitors and their advance in vitro and in vivo assessment in the future.

Abstract Image

基于吡咯[2,1-f][1,2,4]三嗪和1-(甲基哌啶-4-基)苯胺类似物的新型杂种化合物的设计与开发:通过MERTK抑制探索作为抗癌药物的效用。
mer -酪氨酸激酶(MERTK)是AXL, TYRO3和MERTK (TAM)家族的成员,是癌症治疗的有希望的靶点之一。它在癌细胞存活和增殖中起关键作用,并调节癌症的免疫反应。本研究旨在根据MERTK的药理作用要求,采用多重合成的方法,对单个药效团进行杂交,合理设计和开发分子。采用杂化药物设计方法,将吡咯[2,1-f][1,2,4]三嗪与1-(甲基哌啶-4-基)苯胺药效体系杂交,开发出新型先导物(1K1-1K5)。这些分子是通过多步合成方法合成的。通过细胞活力、药物代谢和药代动力学(DMPK)以及MERTK抑制研究来评估合成分子的药理学潜力。IK5对A549细胞的IC50值为0.36 μM,其次是MCF-7和MDA-MB-231细胞的IC50值分别为0.42 μM和0.80 μM。此外,还分析了这些分子的微粒体稳定性,发现它们具有更好的内在清除率。因此,这些分子为开发新的MERTK抑制剂及其在体外和体内评估中的进展铺平了道路。
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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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