Background/Objective: Oncogenic tyrosine kinases (TKs) such as ALK and SRC promote cancer progression, but their effects on metabolic enzymes are still not well understood. This study examines how TK signaling regulates inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, and assesses its potential as a therapeutic target. Methods: Phosphoproteomic screening and in vitro kinase assays were used to identify phosphorylation sites on IMPDH2. Lipid-binding assays explored the role of phosphatidylinositol 3-phosphate (PI3P) in IMPDH2 regulation. Structure-based virtual screening discovered small-molecule allosteric inhibitors, which were tested in lymphoma cell models, including ALK and BTK-inhibitor resistant lines. Results: Here, we identify Inosine monophosphate dehydrogenase-2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, as a novel substrate of ALK and SRC. We show that phosphorylation at the conserved Y233 residue within the allosteric domain enhances IMPDH2 activity, linking TK signaling to metabolic reprogramming in cancer cells. We further identify PI3P as a natural lipid inhibitor that binds IMPDH2 and suppresses its enzymatic function. Using structure-based virtual screening, we developed Comp-10, a first-in-class allosteric IMPDH inhibitor. Unlike classical active-site inhibitors such as mycophenolic acid (MPA), Comp-10 decreases IMPDH1/2 protein levels, blocks filament (rod/ring) formation, and inhibits the growth of ALK and BTK inhibitor-resistant lymphoma cells. Comp-10 acts post-transcriptionally and avoids compensatory IMPDH upregulation observed with MPA (rod/ring) formation, and inhibited growth in TKI-resistant lymphoma cells. Notably, Comp-10 avoided the compensatory IMPDH upregulation observed with MPA. Conclusion: These findings uncover a novel TK–IMPDH2 signaling axis and provide mechanistic and therapeutic insight into the allosteric regulation of IMPDH2. Comp-10 represents a promising therapeutic candidate for targeting metabolic vulnerabilities in tyrosine kinase driven cancers.
背景/目的：致癌性酪氨酸激酶（如ALK和SRC）可促进癌症进展，但其对代谢酶的调控机制尚不明确。本研究探讨了酪氨酸激酶信号如何调控嘌呤合成限速酶肌苷一磷酸脱氢酶2（IMPDH2），并评估其作为治疗靶点的潜力。方法：通过磷酸化蛋白质组学筛选及体外激酶实验鉴定IMPDH2的磷酸化位点；采用脂质结合实验探究磷脂酰肌醇3-磷酸（PI3P）对IMPDH2的调控作用；基于结构的虚拟筛选发现小分子变构抑制剂，并在淋巴瘤细胞模型（包括ALK与BTK抑制剂耐药株）中进行验证。结果：本研究首次证实嘌呤合成限速酶IMPDH2是ALK与SRC的新型底物。保守的变构结构域Y233位点磷酸化可增强IMPDH2活性，从而将酪氨酸激酶信号与癌细胞代谢重编程相连接。进一步发现PI3P作为天然脂质抑制剂，可通过结合IMPDH2抑制其酶活性。通过基于结构的虚拟筛选，我们开发出首创新型变构IMPDH抑制剂Comp-10。与霉酚酸（MPA）等经典活性位点抑制剂不同，Comp-10能降低IMPDH1/2蛋白水平，阻断丝状结构（杆状/环状）形成，并抑制ALK与BTK抑制剂耐药淋巴瘤细胞的生长。该化合物在转录后水平发挥作用，可避免MPA治疗中出现的代偿性IMPDH上调现象。结论：本研究揭示了酪氨酸激酶-IMPDH2新型信号轴，为IMPDH2的变构调控机制提供了理论依据和治疗思路。Comp-10有望成为靶向酪氨酸激酶驱动型癌症代谢脆弱性的潜在治疗候选药物。
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