![\"\"](\"https:\/\/sites.unica.it\/pe2026\/files\/2026\/05\/Van-Hauwermeiren-Anouk-768x1024.jpeg\")
<\/figure>OC27 – Anouk Van Hauwermeiren<\/strong><\/p>\n\n\n\n Ghent University, Belgium<\/p>\n\n\n\n e-mail<\/a> – LinkedIn<\/a><\/strong> –<\/strong> ORCID<\/a><\/strong><\/p>\n<\/div><\/div>\n\n\n\n <\/p>\n\n\n\n <\/p>\n","protected":false},"excerpt":{"rendered":" OC27 – Anouk Van Hauwermeiren Ghent University, Belgium e-mail – LinkedIn – ORCID Macrocyclization as a strategy for optimizing protacs targeting Aurora Kinase A Anouk Van Hauwermeiren1, Simon Krols1, Fien Martens2, Hanne Van De Putte1, Muhammad […]<\/p>\n","protected":false},"author":9643,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-1765","post","type-post","status-publish","format-standard","hentry","category-senza-categoria"],"_links":{"self":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1765","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/users\/9643"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/comments?post=1765"}],"version-history":[{"count":4,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1765\/revisions"}],"predecessor-version":[{"id":1816,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1765\/revisions\/1816"}],"wp:attachment":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/media?parent=1765"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/categories?post=1765"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/tags?post=1765"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}Macrocyclization as a strategy for optimizing protacs targeting Aurora Kinase A<\/strong><\/strong><\/td><\/tr> Anouk Van Hauwermeiren1<\/sup>, Simon Krols1<\/sup>, Fien Martens2<\/sup>, Hanne Van De Putte1<\/sup>, Muhammad Rishifi2<\/sup>, Kaat Durinck2<\/sup>, Serge Van Calenbergh1<\/sup>
<\/em>
1<\/sup><\/em> Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Belgium;
2<\/sup><\/em> Department of Biomolecular Medicine, Faculty of Medicine & Health Sciences, Ghent University, Belgium<\/td><\/tr>Abstract<\/strong>
Previous efforts at the Laboratory for Medicinal Chemistry led to the discovery of proteolysis-targeting chimeras (PROTACs) directed against Aurora kinase A (AURKA). Although these demonstrated potent in vitro degradation activity in neuroblastoma cell lines, their in vivo efficacy was limited, primarily due to poor metabolic stability, which hindered further development. [1]
To address this limitation, macrocyclization was explored as a structural optimization strategy. By restricting conformational flexibility and limiting enzymatic accessibility, macrocyclization may improve the potency, selectivity, and metabolic stability of small molecules. [2\u20133] Guided by the co-crystal structure of the selective AURKA inhibitor MK-5108 bound to its target (figure 1), a series of macrocyclic AURKA ligands was designed, synthesized, and elaborated into AURKA-targeting PROTACs. Biological evaluation demonstrated that these macrocyclic PROTACs retained degradation potency comparable to their non-macrocyclic counterparts, indicating that macrocyclization is well tolerated within the PROTAC context. Notably, the macrocyclic PROTACs exhibited significantly improved metabolic stability, particularly with regard to cytochrome P450-mediated metabolism. Collectively, these findings highlight macrocyclization as a promising strategy to optimize PROTACs for improved pharmacokinetic properties.
![\"\"](\"http:\/\/sites.unica.it\/pe2026\/files\/2026\/05\/Figure-1.-Co-crystal-structure-of-MK-51088-bound-to-AURKA.png\")
Figure 1. Co-crystal structure of MK-5108 bound to AURKA<\/td><\/tr>References <\/strong>
[1] Krols S, Rishfi M, et al. Second-Generation AURKA-Targeting PROTACs: Structural Optimization toward in Vivo Degradation in Neuroblastoma. J Med Chem. 2025 Nov 27;68(22):23962\u201376. doi:10.1021\/acs.jmedchem.5c01271
[2] Driggers EM, Hale SP, et al. The exploration of macrocycles for drug discovery \u2014 an underexploited structural class. Nat Rev Drug Discov. 2008 Jul;7(7):608\u201324. doi:10.1038\/nrd2590
[3] Amrhein JA, Knapp S, et al. Synthetic Opportunities and Challenges for Macrocyclic Kinase Inhibitors. J Med Chem. 2021 Jun 24;64(12):7991\u20138009. doi:10.1021\/acs.jmedchem.1c00217<\/td><\/tr><\/tbody><\/table><\/div><\/figure>\n\n\n\n