Sivakumaren Sindhu Carmen, Shim Hyeseok, Zhang Tinghu, Ferguson Fleur M, Lundquist Mark R, Browne Christopher M, Seo Hyuk-Soo, Paddock Marcia N, Manz Theresa D, Jiang Baishan, Hao Ming-Feng, Krishnan Pranav, Wang Diana G, Yang T Jonathan, Kwiatkowski Nicholas P, Ficarro Scott B, Cunningham James M, Marto Jarrod A, Dhe-Paganon Sirano, Cantley Lewis C, Gray Nathanael S
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY 10065, USA.
Cell Chem Biol. 2020 May 21;27(5):525-537.e6. doi: 10.1016/j.chembiol.2020.02.003. Epub 2020 Mar 3.
The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here, we present the discovery and characterization of a pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.
PI5P4K已被证明对癌细胞增殖和其他疾病很重要。然而，由于缺乏有效的、特异性的小分子，针对这些激酶的治疗潜力尚未得到充分研究。在此，我们介绍了一种泛PI5P4K抑制剂THZ-P1-2的发现和特性，它共价靶向PI5P4Kα/β/γ中一个无序环上的半胱氨酸。THZ-P1-2在整个激酶组中表现出有限的脱靶效应的细胞靶向作用。AML/ALL细胞系对THZ-P1-2敏感，这与PI5P4K在白血病发生中的报道作用一致。THZ-P1-2导致自噬体清除缺陷以及TFEB核定位和靶基因上调，以共价依赖的方式破坏自噬，并模拟PI5P4K基因缺失的效应。我们的研究表明，PI5P4K是易于处理的靶点，THZ-P1-2作为一种有用的工具，可进一步探究PI5P4K抑制的治疗潜力，并为这些脂质激酶在癌症代谢和其他自噬依赖性疾病中的药物发现活动提供信息。
