THZ-P1-2 is a potent inhibitor of PI5P4K kinase, with the IC50 values of 0.95μM and 5.9μM for PI5P4Kα and PI5P4Kβ, respectively [1]. THZ-P1-2 binds in the active site and covalently modifies cysteine residues of the PI5P4K kinases[2]. THZ-P1-2 has been widely used in cell models to regulate autophagy[3].
In vitro, THZ-P1-2 treatment for 4 hours inhibited SARS-CoV-2 replication in Calu-3 cells with an EC50 value of 0.2µM and inhibited cell viability (CC50=16µM)[4]. THZ-P1-2 treatment (6.4µM) for 48h significantly inhibited NB4 cell viability and enhanced venetoclax-induced apoptosis[5]. Treatment with 6.4µM THZ-P1-2 for 72h significantly reduced Jurkat cell viability and induced DNA damage, triggered apoptosis, and disrupted mitochondrial homeostasis and autophagic flux in cells[6].
References:
[1] Manz T D, Sivakumaren S C, Yasgar A, et al. Structure–activity relationship study of covalent pan-phosphatidylinositol 5-phosphate 4-kinase inhibitors[J]. ACS medicinal chemistry letters, 2019, 11(3): 346-352.
[2] Sivakumaren S C, Shim H, Zhang T, et al. Targeting the PI5P4K lipid kinase family in cancer using covalent inhibitors[J]. Cell chemical biology, 2020, 27(5): 525-537. e6.
[3] Lima K, Nogueira F L, Cipelli M, et al. Potency and efficacy of pharmacological PIP4K2 inhibitors in acute lymphoblastic leukemia[J]. European Journal of Pharmacology, 2024, 977: 176723.
[4] Karim M, Mishra M, Lo C W, et al. PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2[J]. Nature Communications, 2025, 16(1): 6397.
[5] Lima K, Carvalho M F L, Pereira-Martins D A, et al. Pharmacological inhibition of PIP4K2 potentiates venetoclax-induced apoptosis in acute myeloid leukemia[J]. International Journal of Molecular Sciences, 2023, 24(23): 16899.
[6] Lima K, Pereira-Martins D A, de Miranda L B L, et al. The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy[J]. Blood cancer journal, 2022, 12(11): 151.
THZ-P1-2 是一种有效的PI5P4K激酶抑制剂，对PI5P4Kα和PI5P4Kβ的IC50值分别为0.95μM和5.9μM[1]。THZ-P1-2通过结合于PI5P4K激酶的活性位点，共价修饰半胱氨酸残基[2]。THZ-P1-2已在细胞模型中广泛应用于调控自噬过程[3]。
在体外，使用THZ-P1-2处理Calu-3细胞4小时可抑制SARS-CoV-2病毒复制，EC50值为0.2µM，同时对细胞活力产生抑制（CC50=16µM）[4]。以6.4µM的THZ-P1-2处理NB4细胞48小时能显著抑制细胞活力，并增强Venetoclax诱导的细胞凋亡[5]。使用6.4µM的THZ-P1-2处理Jurkat细胞72小时可显著降低细胞活力，诱导DNA损伤，触发细胞凋亡，并破坏线粒体稳态及自噬通量[6]。