Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling,Journal of Medicinal Chemistry

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Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-02-01 , DOI: 10.1021/acs.jmedchem.1c01265
Tamas Yelland ₁ , Esther Garcia ₁ , Charles Parry ₂ , Dominika Kowalczyk ₁ , Marta Wojnowska ₃ , Andrea Gohlke ₂ , Matja Zalar _{2,

4} , Kenneth Cameron ₂ , Gillian Goodwin _{2,

5} , Qing Yu ₆ , Peng-Cheng Zhu ₆ , Yasmin ElMaghloob ₁ , Angelo Pugliese _{2,

5} , Lewis Archibald ₇ , Andrew Jamieson ₇ , Yong Xiang Chen ₆ , Duncan McArthur _{2,

5} , Justin Bower ₂ , Shehab Ismail _{1,

8}

Affiliation

RAS is a major anticancer drug target which requires membrane localization to activate downstream signal transduction. The direct inhibition of RAS has proven to be challenging. Here, we present a novel strategy for targeting RAS by stabilizing its interaction with the prenyl-binding protein PDE6D and disrupting its localization. Using rationally designed RAS point mutations, we were able to stabilize the RAS:PDE6D complex by increasing the affinity of RAS for PDE6D, which resulted in the redirection of RAS to the cytoplasm and the primary cilium and inhibition of oncogenic RAS/ERK signaling. We developed an SPR fragment screening and identified fragments that bind at the KRAS:PDE6D interface, as shown through cocrystal structures. Finally, we show that the stoichiometric ratios of KRAS:PDE6D vary in different cell lines, suggesting that the impact of this strategy might be cell-type-dependent. This study forms the foundation from which a potential anticancer small-molecule RAS:PDE6D complex stabilizer could be developed.

中文翻译：

RAS:PDE6D 复合物的稳定是一种抑制 RAS 信号传导的新策略

RAS 是一种主要的抗癌药物靶点，需要膜定位以激活下游信号转导。RAS的直接抑制已被证明具有挑战性。在这里，我们提出了一种通过稳定其与异戊二烯结合蛋白 PDE6D 的相互作用并破坏其定位来靶向 RAS 的新策略。使用合理设计的 RAS 点突变，我们能够通过增加 RAS 对 PDE6D 的亲和力来稳定 RAS：PDE6D 复合物，这导致 RAS 重新定向到细胞质和初级纤毛并抑制致癌 RAS/ERK 信号传导。我们开发了 SPR 片段筛选并确定了在 KRAS:PDE6D 界面结合的片段，如通过共晶结构所示。最后，我们表明 KRAS:PDE6D 的化学计量比在不同的细胞系中有所不同，表明该策略的影响可能与细胞类型有关。这项研究为开发潜在的抗癌小分子 RAS:PDE6D 复合稳定剂奠定了基础。

更新日期：2022-02-10

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