Hillebrand Laura, Wang Guiqun, Rasch Alexander, Masberg Benedikt, Chaikuad Apirat, Kronenberger Thales, Günther Ellen, Forster Michael, Poso Antti, Lämmerhofer Michael, Laufer Stefan A, Knapp Stefan, Gehringer Matthias
Faculty of Medicine, Institute of Biomedical Engineering, Department for Medicinal Chemistry, Eberhard Karls University Tübingen Auf der Morgenstelle 8 D-72076 Tübingen Germany
Cluster of Excellence iFIT (EXC 2180) "Image-Guided & Functionally Instructed Tumor Therapies", Eberhard Karls University Tübingen D-72076 Tübingen Germany.
RSC Med Chem. 2025 Aug 1. doi: 10.1039/d5md00440c.
While cysteine targeting in kinases is well established and widely used, covalent interactions with other amino acids remain much less explored. We aimed to develop covalent inhibitors targeting tyrosine residues in the protein kinases JAK3 and MK2 using structure-based design principles to generate small sets of ligands containing tyrosine-reactive sulfonyl fluoride and the less-explored fluorosulfate warheads. While the JAK3 inhibitors failed to achieve covalent binding, the fluorosulfate-bearing MK2 inhibitor 42, which had been designed as an allosteric binder, unexpectedly formed a bond with the "catalytic" lysine, additionally uncovering a unique interaction at the hinge region. This highlights the untapped potential of fluorosulfates and provides a rare example of the use of this electrophile for lysine targeting in kinases. Our results highlight the limitations of traditional design methods and support the integration of fragment/lead-like covalent library screening to discover unanticipated interactions.
虽然激酶中的半胱氨酸靶向已得到充分确立并被广泛应用，但与其他氨基酸的共价相互作用仍有待深入探索。我们旨在利用基于结构的设计原则，开发靶向蛋白激酶JAK3和MK2中酪氨酸残基的共价抑制剂，以生成少量含有酪氨酸反应性磺酰氟和较少研究的氟代硫酸盐弹头的配体。虽然JAK3抑制剂未能实现共价结合，但设计为变构结合剂的含氟代硫酸盐的MK2抑制剂42意外地与“催化”赖氨酸形成了键，此外还在铰链区发现了一种独特的相互作用。这突出了氟代硫酸盐尚未开发的潜力，并提供了一个罕见的例子，即使用这种亲电试剂靶向激酶中的赖氨酸。我们的结果突出了传统设计方法的局限性，并支持整合片段/类先导共价文库筛选以发现意外的相互作用。
