| Structural highlights
Function
[ACK1_HUMAN] Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound 11i is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.
First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia.,Cho H, Shin I, Ju E, Choi S, Hur W, Kim H, Hong E, Kim ND, Choi HG, Gray NS, Sim T J Med Chem. 2018 Sep 11. doi: 10.1021/acs.jmedchem.8b00882. PMID:30153003[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kato J, Kaziro Y, Satoh T. Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation. Biochem Biophys Res Commun. 2000 Feb 5;268(1):141-7. PMID:10652228 doi:http://dx.doi.org/10.1006/bbrc.2000.2106
- ↑ Teo M, Tan L, Lim L, Manser E. The tyrosine kinase ACK1 associates with clathrin-coated vesicles through a binding motif shared by arrestin and other adaptors. J Biol Chem. 2001 May 25;276(21):18392-8. Epub 2001 Feb 27. PMID:11278436 doi:http://dx.doi.org/10.1074/jbc.M008795200
- ↑ Yokoyama N, Lougheed J, Miller WT. Phosphorylation of WASP by the Cdc42-associated kinase ACK1: dual hydroxyamino acid specificity in a tyrosine kinase. J Biol Chem. 2005 Dec 23;280(51):42219-26. Epub 2005 Oct 28. PMID:16257963 doi:http://dx.doi.org/10.1074/jbc.M506996200
- ↑ van der Horst EH, Degenhardt YY, Strelow A, Slavin A, Chinn L, Orf J, Rong M, Li S, See LH, Nguyen KQ, Hoey T, Wesche H, Powers S. Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15901-6. Epub 2005 Oct 24. PMID:16247015 doi:http://dx.doi.org/10.1073/pnas.0508014102
- ↑ Modzelewska K, Newman LP, Desai R, Keely PJ. Ack1 mediates Cdc42-dependent cell migration and signaling to p130Cas. J Biol Chem. 2006 Dec 8;281(49):37527-35. Epub 2006 Oct 12. PMID:17038317 doi:10.1074/jbc.M604342200
- ↑ Yokoyama N, Miller WT. Purification and enzyme activity of ACK1. Methods Enzymol. 2006;406:250-60. PMID:16472662 doi:http://dx.doi.org/10.1016/S0076-6879(06)06018-6
- ↑ Howlin J, Rosenkvist J, Andersson T. TNK2 preserves epidermal growth factor receptor expression on the cell surface and enhances migration and invasion of human breast cancer cells. Breast Cancer Res. 2008;10(2):R36. doi: 10.1186/bcr2087. Epub 2008 Apr 24. PMID:18435854 doi:http://dx.doi.org/10.1186/bcr2087
- ↑ Grovdal LM, Johannessen LE, Rodland MS, Madshus IH, Stang E. Dysregulation of Ack1 inhibits down-regulation of the EGF receptor. Exp Cell Res. 2008 Apr 1;314(6):1292-300. doi: 10.1016/j.yexcr.2007.12.017. Epub , 2008 Jan 5. PMID:18262180 doi:http://dx.doi.org/10.1016/j.yexcr.2007.12.017
- ↑ Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63. doi: 10.1074/jbc.M109.072660. Epub, 2009 Oct 8. PMID:19815557 doi:10.1074/jbc.M109.072660
- ↑ Liu Y, Karaca M, Zhang Z, Gioeli D, Earp HS, Whang YE. Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases. Oncogene. 2010 Jun 3;29(22):3208-16. doi: 10.1038/onc.2010.103. Epub 2010 Apr 12. PMID:20383201 doi:http://dx.doi.org/10.1038/onc.2010.103
- ↑ Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schonbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar 19;5(3):e9646. doi: 10.1371/journal.pone.0009646. PMID:20333297 doi:10.1371/journal.pone.0009646
- ↑ Cho H, Shin I, Ju E, Choi S, Hur W, Kim H, Hong E, Kim ND, Choi HG, Gray NS, Sim T. First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia. J Med Chem. 2018 Sep 11. doi: 10.1021/acs.jmedchem.8b00882. PMID:30153003 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00882
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