PROTACs作为针对靶标蛋白的降解技术已经受到了制药界越来越多的关注。对于这一技术的难点就在于如何将靶标蛋白与E3泛素连接酶配体连接起来。由于DEL技术在筛选化合物时依据的是化合物与靶蛋白亲和力的高低,非常适合用来筛选能与靶蛋白形成高亲和力的化合物,所以,DEL技术可以作为PROTAC中鉴定哪些化合物可以作为靶蛋白配体的有力手段。 X-Chem针对ERα 野生型和3个突变型筛选了1200 亿个 DNA 编码分子,分别在有或没有雌二醇存在的条件下测试其对于 ERα 的亲和力。这种筛选得到了一系列与靶蛋白有作用的化合物,如化合物 12。值得注意的是,所有筛选得到的化合物都包含有苯酚这一结构。筛选之后的再合成得到的化合物13对ERα表现出nM级别的结合、拮抗和降解的能力。 在化合物13上组装上连接链和E3泛素连接酶配体VHL后就能够得到对ERα具有nM降解能力的双特异性化合物14。在小鼠PDX模型中,该化合物能够抑制ER阳性的MCF7肿瘤细胞的生长。这项研究表明,通过 DEL 筛选和小范围的优化,有望得到新颖的双特异性降解剂的先导化合物[17]。 图10:利用DEL筛选PROTAC
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总结
在传统的HTS无法得到理想的苗头化合物时,DEL技术可以作为一个有效的手段继续进行尝试; DEL技术得到的苗头化合物可以通过简单的优化获得临床候选化合物; 尽管在以靶点为导向的先导化合物筛选方面已经积累了很多工作,但是DEL技术只能应用于性能良好的蛋白质靶点。在早期药物发现领域,HTS仍然是应用最多的方法。 参考文献:1.(a) Brenner, S.;Lenner, R. A. Encoded combinatorial chemistry. Proc. Natl. Acad. Sci. USA 1992,89, 5381–5383.(b) Lerner, Richard A.; Neri, Dario. Reflections onDNA-encoded chemical libraries. Biochemicaland Biophysical Research Communications (2020), 527(3), 757-759.2.Madsen,Daniel; Azevedo, Carlos; Micco, Iolanda; Petersen, Lars Kolster; Hansen, NilsJakob Vest. An overview of DNA-encoded libraries: A versatile tool for drugdiscovery. Progress in medicinal chemistry (2020), 59, 181-249.3.Satz, Alexander L.;Kollmann, Christopher S.; Paegel, Brian M. DNA-encoded libraries in thepharmaceutical industry. Medicinal Chemistry Reviews (2020), 55, 547-564.4.Goodnow, R. A. Jr. (ed.) A Handbook for DNA-Encoded Chemistry: Theory andApplications for Exploring Chemical Space and Drug Discovery.Wiley:Hoboken, NJ, 2014.5.Song, Minsoo; Hwang,Gil Tae. DNA-Encoded Library Screening as Core Platform Technology in DrugDiscovery: Its Synthetic Method Development and Applications in DEL Synthesis.Journal of Medicinal Chemistry (2020), 63(13), 6578-6599.6.Conole, Daniel; HHunter, James; J Waring, Michael. The maturation of DNA encoded libraries:opportunities for new users. Future Medicinal Chemistry (2021), 13(2), 173-191.7.Flood,Dillon T.; Kingston, Cian; Vantourout, Julien C.; Dawson, Philip E.; Baran,Phil S. DNA Encoded Libraries: A Visitor's Guide.Israel Journal of Chemistry (2020), 60(3-4), 268-280.8.Decurtins, Willy;Wichert, Moreno; Franzini, Raphael M.; Buller, Fabian; Stravs, Michael A.;Zhang, Yixin; Neri, Dario; Scheuermann, Jorg. Automated screening for smallorganic ligands using DNA-encoded chemical libraries. Nature Protocols (2016),11(4), 764-780.9.Goodnow, R. A., Jr.;Dumelin, C. E.; Keefe, A. D. DNA-encoded chemistry: enabling the deepersampling of chemical space. Nat. Rev. Drug Discovery 2017, 16, 131−147.10.(a) Harris, P. A.;King, B. W.; Bandyopadhyay, D.; Berger, S. B.; Campobasso, N.; Capriotti, C.A.; Cox, J. A.; Dare, L.; Dong, X.; Finger, J. N.; et al. DNA-encoded libraryscreening identifies benzo[b][1,4]oxazepin-4-ones as highly potent andmonoselective receptor interacting protein 1 kinase inhibitors. J. Med. Chem. 2016, 59, 2163–2178. (b) Satz,A. What do you get from DNA-encoded libraries? ACS Med. Chem. Lett. 2018,9, 408–410. 11.Harris, Philip A.;Marinis, Jill M.; Lich, John D.; Berger, Scott B.; Chirala, Anirudh; Cox, JulieA.; Eidam, Patrick M.; Finger, Joshua N.; Gough, Peter J.; Jeong, Jae U.; et al.Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) forthe Treatment of Pancreatic Cancer. ACS Medicinal Chemistry Letters (2019),10(6), 857-862.12.(a) Belyanskaya, S. L.; Ding, Y.; Callahan, J.F.; Lazaar, A. 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Y.; Fiez-Vandal, Cedric; Schlenker, Oliver; Edman, Karl; Aggeler,Birte; Brown, Dean G.; Brown, Giles A.; Cooke, Robert M.; Dumelin, ChristophE.; Dore, Andrew S.; et al. Structural insight into allosteric modulation ofprotease-activated receptor 2. Nature (London, United Kingdom) (2017),545(7652), 112-115.15.Ahn,Seungkirl; Kahsai, Alem W.; Pani, Biswaranjan; Wang, Qin-Ting; Zhao, Shuai;Wall, Alissa L.; Strachan, Ryan T.; Staus, Dean P.; Wingler, Laura M.; Sun, LillianD.; et al. Allosteric "beta-blocker" isolated from a DNA-encodedsmall molecule library. Proceedings of the National Academy of Sciences of theUnited States of America (2017), 114(7), 1708-1713.16.Ahn,Seungkirl; Pani, Biswaranjan; Kahsai, Alem W.; Olsen, Eva K.; Husemoen, Gitte;Vestergaard, Mikkel; Jin, Lei; Zhao, Shuai; Wingler, Laura M.; Rambarat, PaulaK.; et al. Small-Molecule Positive Allosteric Modulators of the β2-AdrenoceptorIsolated from DNA-Encoded Libraries. 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