Titulaer Willem H C, Klindert Sebastian, Taylor Corey, Schwab Rebekka A, Siebold Christian, Kolb Peter
Pharmaceutical Chemistry, University of Marburg, Marburg, 35037, Germany.
Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, United Kingdom.
Eur J Med Chem. 2025 Oct 15;296:117753. doi: 10.1016/j.ejmech.2025.117753. Epub 2025 May 27.
The G protein-coupled receptor Smoothened (SMO) plays a pivotal role in embryonic development transducing the Hedgehog morphogen signal into the cell. Aberrant activation of the pathway is associated with various cancer types. Antagonizing SMO has been recognized as a therapeutic strategy exemplified by drugs such as vismodegib and sonidegib, but despite initial remission, cancer recurrence is frequent due to resistance mutations. Utilizing a structure-based design approach, we have identified three unprecedented chemotypes to antagonize SMO with potencies in the low micromolar range. In total, 67 compounds identified through molecular docking were assayed in four rounds with hit rates of 27% and 63% during hit identification, i.e. the first two rounds. Importantly, the potency of ligands with two of the chemotypes identified in this work is not strongly affected by the vismodegib resistance mutation D473G. The mutation affects potency and maximal inhibitory effect of these ligands only in a way similar to SANT-1, a SMO ligand unencumbered by the mutation. Our study thus shows a successful application of structure-based design for the discovery of novel SMO antagonist chemotypes.
G蛋白偶联受体Smoothened（SMO）在胚胎发育过程中发挥关键作用，将Hedgehog形态发生素信号转导至细胞内。该信号通路的异常激活与多种癌症类型相关。拮抗SMO已被确认为一种治疗策略，维莫德吉和索尼德吉等药物就是例证，但尽管初期有缓解效果，由于耐药性突变，癌症复发很常见。利用基于结构的设计方法，我们已鉴定出三种前所未有的化学类型，可在低微摩尔范围内有效拮抗SMO。通过分子对接总共鉴定出67种化合物，并分四轮进行检测，在命中鉴定阶段（即前两轮）的命中率分别为27%和63%。重要的是，本研究中鉴定出的两种化学类型的配体效力不受维莫德吉耐药性突变D473G的强烈影响。该突变对这些配体效力和最大抑制作用的影响方式，仅与不受该突变影响的SMO配体SANT-1类似。因此，我们的研究表明基于结构的设计在发现新型SMO拮抗剂化学类型方面的成功应用。
