| Structural highlights
Disease
PI42A_HUMAN Precursor B-cell acute lymphoblastic leukemia.
Function
PI42A_HUMAN Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). May exert its function by regulating the levels of PtdIns5P, which functions in the cytosol by increasing AKT activity and in the nucleus signals through ING2. May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation. May negatively regulate insulin-stimulated glucose uptake by lowering the levels of PtdIns5P. May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size.[1]
Publication Abstract from PubMed
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.
Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A.,Wortmann L, Brauer N, Holton SJ, Irlbacher H, Weiske J, Lechner C, Meier R, Karen J, Sioberg CB, Putter V, Christ CD, Ter Laak A, Lienau P, Lesche R, Nicke B, Cheung SH, Bauser M, Haegebarth A, von Nussbaum F, Mumberg D, Lemos C J Med Chem. 2021 Nov 11;64(21):15883-15911. doi: 10.1021/acs.jmedchem.1c01245., Epub 2021 Oct 26. PMID:34699202[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wilcox A, Hinchliffe KA. Regulation of extranuclear PtdIns5P production by phosphatidylinositol phosphate 4-kinase 2alpha. FEBS Lett. 2008 Apr 16;582(9):1391-4. doi: 10.1016/j.febslet.2008.03.022. Epub, 2008 Mar 24. PMID:18364242 doi:http://dx.doi.org/10.1016/j.febslet.2008.03.022
- ↑ Wortmann L, Brauer N, Holton SJ, Irlbacher H, Weiske J, Lechner C, Meier R, Karen J, Sioberg CB, Putter V, Christ CD, Ter Laak A, Lienau P, Lesche R, Nicke B, Cheung SH, Bauser M, Haegebarth A, von Nussbaum F, Mumberg D, Lemos C. Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A. J Med Chem. 2021 Nov 11;64(21):15883-15911. doi: 10.1021/acs.jmedchem.1c01245., Epub 2021 Oct 26. PMID:34699202 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01245
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