Throup Adam, Zraikat Manar Saleh, Gordon Andrew, Jafarinejad Soumehsaraei Shohreh, Haase Kathrin D, Patterson Laurence H, Cooper Patricia A, Hanlon Katherine, Loadman Paul M, Sutherland Mark, Shnyder Steven D, Sheldrake Helen M
Institute of Cancer Therapeutics, University of Bradford Bradford BD7 1DP UK
RSC Med Chem. 2024 Sep 13;15(10):3616-24. doi: 10.1039/d4md00306c.
The integrin family of cell surface extracellular matrix binding proteins are key to several physiological processes involved in tissue development, as well as cancer proliferation and dissemination. They are therefore attractive targets for drug discovery with cancer and non-cancer applications. We have developed a new integrin antagonist chemotype incorporating a functionalised cyclobutane ring as the central scaffold in an arginine-glycine-aspartic acid mimetic structure. Here, we report the synthesis of cyclobutanecarboxylic acids and cyclobutylamines with tetrahydronaphthyridine and aminopyridine arginine mimetic sidechains and masked carboxylic acid aspartic acid mimetic sidechains of varying length. Effective αvβ3 antagonists and new aspartic acid mimetics were identified in cell-based adhesion and invasion assays. A lead compound selected based on activity (IC < 1 μM), stability ( > 80 minutes) and synthetic tractability was well-tolerated . These results show the promise of this synthetic approach for developing αvβ3 antagonists and provide a firm foundation to progress into advanced preclinical evaluation prior to progression towards the clinic. Additionally, they highlight the use of functionalised cyclobutanes as metabolically stable core structures and a straightforward and robust method for their synthesis. This important contribution to the medicinal chemists' toolbox paves the way for increased use of cyclobutanes in drug discovery.
细胞表面细胞外基质结合蛋白的整合素家族对于组织发育以及癌症增殖和扩散所涉及的多个生理过程至关重要。因此，它们是癌症和非癌症应用药物研发的有吸引力的靶点。我们开发了一种新的整合素拮抗剂化学类型，其在精氨酸 - 甘氨酸 - 天冬氨酸模拟结构中引入了功能化的环丁烷环作为中心支架。在此，我们报告了带有四氢萘啶和氨基吡啶精氨酸模拟侧链以及不同长度的掩蔽羧酸天冬氨酸模拟侧链的环丁烷羧酸和环丁胺的合成。在基于细胞的黏附与侵袭试验中鉴定出了有效的αvβ3拮抗剂和新的天冬氨酸模拟物。基于活性（IC < 1 μM）、稳定性（> 80分钟）和合成可操作性选择的先导化合物耐受性良好。这些结果显示了这种合成方法在开发αvβ3拮抗剂方面的前景，并为在进入临床前朝着高级临床前评估推进提供了坚实基础。此外，它们突出了功能化环丁烷作为代谢稳定核心结构的用途以及一种直接且强大的合成方法。这对药物化学家工具箱的这一重要贡献为环丁烷在药物研发中的更多应用铺平了道路。
