Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A,Journal of Medicinal Chemistry

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Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-26 , DOI: 10.1021/acs.jmedchem.1c01245
Lars Wortmann ₁ , Nico Bräuer ₁ , Simon J Holton ₁ , Horst Irlbacher ₁ , Jörg Weiske ₁ , Christian Lechner ₁ , Robin Meier ₁ , Jakob Karén ₂ , Catrine Berthold Siöberg ₂ , Vera Pütter ₁ , Clara D Christ ₁ , Antonius Ter Laak ₁ , Philip Lienau ₁ , Ralf Lesche ₁ , Barbara Nicke ₁ , Shing-Hu Cheung ₁ , Marcus Bauser ₁ , Andrea Haegebarth ₁ , Franz von Nussbaum ₁ , Dominik Mumberg ₁ , Clara Lemos ₁

Affiliation

PIP4K2A is an insufficiently studied type II lipid kinase that catalyzes the conversion of phosphatidylinositol-5-phosphate (PI5P) into phosphatidylinositol 4,5-bisphosphate (PI4,5P₂). The involvement of PIP4K2A/B in cancer has been suggested, particularly in the context of p53 mutant/null tumors. PIP4K2A/B depletion has been shown to induce tumor growth inhibition, possibly due to hyperactivation of AKT and reactive oxygen species-mediated apoptosis. Herein, we report the identification of the novel potent and highly selective inhibitors BAY-091 and BAY-297 of the kinase PIP4K2A by high-throughput screening and subsequent structure-based optimization. Cellular target engagement of BAY-091 and BAY-297 was demonstrated using cellular thermal shift assay technology. However, inhibition of PIP4K2A with BAY-091 or BAY-297 did not translate into the hypothesized mode of action and antiproliferative activity in p53-deficient tumor cells. Therefore, BAY-091 and BAY-297 serve as valuable chemical probes to study PIP4K2A signaling and its involvement in pathophysiological conditions such as cancer.

中文翻译：

激酶 PIP4K2A 的强效和高选择性 1,7-萘啶基抑制剂 BAY-091 和 BAY-297 的发现和表征

PIP4K2A 是一种研究不足的 II 型脂质激酶，可催化 5-磷酸磷脂酰肌醇 (PI5P) 转化为 4,5-二磷酸磷脂酰肌醇 (PI4,5P ₂）。已经提出 PIP4K2A/B 参与癌症，特别是在 p53 突变/无效肿瘤的背景下。PIP4K2A/B 耗竭已显示可诱导肿瘤生长抑制，这可能是由于 AKT 的过度活化和活性氧介导的细胞凋亡。在此，我们报告了通过高通量筛选和随后的基于结构的优化鉴定激酶 PIP4K2A 的新型强效和高选择性抑制剂 BAY-091 和 BAY-297。使用细胞热位移测定技术证明了 BAY-091 和 BAY-297 的细胞靶标接合。然而，用 BAY-091 或 BAY-297 抑制 PIP4K2A 并没有转化为 p53 缺陷肿瘤细胞中假设的作用模式和抗增殖活性。所以，

更新日期：2021-11-11

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