Rational In Silico Design of Selective TMPRSS6 Peptidomimetic Inhibitors via Exploitation of the S2 Subpocket,Journal of Medicinal Chemistry

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Rational In Silico Design of Selective TMPRSS6 Peptidomimetic Inhibitors via Exploitation of the S2 Subpocket
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-19 , DOI: 10.1021/acs.jmedchem.4c00922
Michael Desgagné ₁ , Antoine Désilets ₁ , Sára Ferková ₁ , Matthieu Lepage ₁ , Olivier Perreault ₁ , Alexandre Joushomme ₁ , Gabriel Lemieux ₁ , Walid Guerrab ₁ , Ulrike Froehlich ₁ , Christian Comeau ₁ , Philippe Sarret ₁ , Richard Leduc ₁ , Pierre-Luc Boudreault ₁

Affiliation

TMPRSS6 is a potential therapeutic target for the treatment of iron overload due to its role in regulating levels of hepcidin. Although potent TMPRSS6 inhibitors have been previously developed, their lack of specificity requires optimization to avoid potential side effects before pursuing preclinical development with in vivo models. Here, using computer-aided drug design based on a TMPRSS6 homology model, we reveal that the S2 position of TMPRSS6 offers a potential avenue to achieve selectivity against other members of the TTSP family. Accordingly, we synthesized novel peptidomimetic molecules containing lipophilic amino acids at the P2 position to exploit this unexplored pocket. This enabled us to identify TMPRSS6-selective small molecules with low nanomolar affinity. Finally, pharmacokinetic parameters were determined, and a compound was found to be potent in cellulo toward its primary target while retaining TTSP-subtype selectivity and showing no signs of alteration in in vitro TEER experiments.

中文翻译：

通过利用 S2 子口袋对选择性 TMPRSS6 拟肽抑制剂进行合理的计算机设计

TMPRSS6 由于其在调节铁调素水平方面的作用而成为治疗铁过载的潜在治疗靶点。尽管之前已经开发出有效的 TMPRSS6 抑制剂，但它们缺乏特异性，需要在利用体内模型进行临床前开发之前进行优化以避免潜在的副作用。在这里，使用基于 TMPRSS6 同源模型的计算机辅助药物设计，我们揭示了 TMPRSS6 的 S2 位置提供了实现针对 TTSP 家族其他成员的选择性的潜在途径。因此，我们合成了在 P2 位点含有亲脂性氨基酸的新型拟肽分子，以利用这个未开发的口袋。这使我们能够识别具有低纳摩尔亲和力的 TMPRSS6 选择性小分子。最后，确定了药代动力学参数，发现一种化合物在纤维素中对其主要靶标有效，同时保留 TTSP 亚型选择性，并且在体外TEER 实验中没有显示出改变的迹象。

更新日期：2024-07-19

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