肿瘤代谢物积累驱动的条件共价致死,ACS Chemical Biology

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肿瘤代谢物积累驱动的条件共价致死
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2022-10-03 , DOI: 10.1021/acschembio.2c00384
Minervo Perez ₁ , Kellie D Nance ₁ , Daniel W Bak ₂ , Supuni Thalalla Gamage ₁ , Susana S Najera _{1,

3} , Amy N Conte ₁ , W Marston Linehan ₃ , Eranthie Weerapana ₂ , Jordan L Meier ₁

Affiliation

遗传性平滑肌瘤病和肾细胞癌（HLRCC）是一种由抑癌基因富马酸水合酶（FH）突变驱动的癌症易感综合征。FH 失活会导致亲电致癌代谢物富马酸盐的积累。在缺乏重新激活方法的情况下，可以通过使用遗传筛选鉴定合成致死相互作用来靶向肿瘤抑制因子。受化学蛋白质组靶标识别最新进展的启发，我们在这里测试了一个假设，即 HLRCC 代谢组的亲电性可能会对共价小分子产生独特的敏感性，我们将这种现象称为条件共价致死性。通过筛选一组化学上多样化的亲电子试剂，我们鉴定了一种共价配体 MP-1，它表现出 FH 依赖性细胞毒性。合成和结构-活性分析确定了分子作用的关键分子决定因素。半胱氨酸反应性的化学蛋白质组学分析与可点击探针一起验证了 MP-1 与一系列功能性半胱氨酸结合的能力，其中包括位于 tRNA 甲基转移酶 TRMT1 的 Zn 指结构域中的半胱氨酸。TRMT1 过表达可挽救 tRNA 甲基化免受 MP-1 的抑制，并部分减弱共价配体的细胞毒性。我们的研究强调了共价代谢物和小分子协同产生新型合成致死相互作用的潜力，并提高了应用表型筛选和化学蛋白质组靶点鉴定来鉴定新的功能性肿瘤代谢物靶点的可能性。

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Conditional Covalent Lethality Driven by Oncometabolite Accumulation

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a cancer predisposition syndrome driven by mutation of the tumor suppressor fumarate hydratase (FH). Inactivation of FH causes accumulation of the electrophilic oncometabolite fumarate. In the absence of methods for reactivation, tumor suppressors can be targeted via identification of synthetic lethal interactions using genetic screens. Inspired by recent advances in chemoproteomic target identification, here, we test the hypothesis that the electrophilicity of the HLRCC metabolome may produce unique susceptibilities to covalent small molecules, a phenomenon we term conditional covalent lethality. Screening a panel of chemically diverse electrophiles, we identified a covalent ligand, MP-1, that exhibits FH-dependent cytotoxicity. Synthesis and structure–activity profiling identified key molecular determinants underlying the molecule’s effects. Chemoproteomic profiling of cysteine reactivity together with clickable probes validated the ability of MP-1 to engage an array of functional cysteines, including one lying in the Zn-finger domain of the tRNA methyltransferase enzyme TRMT1. TRMT1 overexpression rescues tRNA methylation from inhibition by MP-1 and partially attenuates the covalent ligand’s cytotoxicity. Our studies highlight the potential for covalent metabolites and small molecules to synergistically produce novel synthetic lethal interactions and raise the possibility of applying phenotypic screening with chemoproteomic target identification to identify new functional oncometabolite targets.

更新日期：2022-10-03

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