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Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site.

Yang J, Campobasso N, Biju MP, Fisher K, Pan XQ, Cottom J, Galbraith S, Ho T, Zhang H, Hong X, Ward P, Hofmann G, Siegfried B, Zappacosta F, Washio Y, Cao P, Qu J, Bertrand S, Wang DY, Head MS, Li H, Moores S, Lai Z, Johanson K, Burton G, Erickson-Miller C, Simpson G, Tummino P, Copeland RA, Oliff A
Chem Biol 18 177-86 (2011)
Cited: 70 times
EuropePMC logo PMID: 21338916

Abstract

c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

Reviews - 3pyy mentioned but not cited (1)

  1. Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families. Li L, Meyer C, Zhou ZW, Elmezayen A, Westover K. J Mol Biol 434 167626 (2022)

Articles - 3pyy mentioned but not cited (18)

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Reviews citing this publication (8)

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  6. Protein Lipidation in Cell Signaling and Diseases: Function, Regulation, and Therapeutic Opportunities. Chen B, Sun Y, Niu J, Jarugumilli GK, Wu X. Cell Chem Biol 25 817-831 (2018)
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  8. The Dominant Mechanism of Cyclophosphamide-Induced Damage to Ovarian Reserve: Premature Activation or Apoptosis of Primordial Follicles? Xie Q, Liao Q, Wang L, Zhang Y, Chen J, Bai H, Li K, Ai J. Reprod Sci (2023)

Articles citing this publication (43)

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  10. c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells. Dunn DM, Woodford MR, Truman AW, Jensen SM, Schulman J, Caza T, Remillard TC, Loiselle D, Wolfgeher D, Blagg BS, Franco L, Haystead TA, Daturpalli S, Mayer MP, Trepel JB, Morgan RM, Prodromou C, Kron SJ, Panaretou B, Stetler-Stevenson WG, Landas SK, Neckers L, Bratslavsky G, Bourboulia D, Mollapour M. Cell Rep 12 1006-1018 (2015)
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  12. C-Abl inhibitor imatinib enhances insulin production by β cells: c-Abl negatively regulates insulin production via interfering with the expression of NKx2.2 and GLUT-2. Xia CQ, Zhang P, Li S, Yuan L, Xia T, Xie C, Clare-Salzler MJ. PLoS ONE 9 e97694 (2014)
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  14. Comment Allosteric BCR-ABL inhibitors in Philadelphia chromosome-positive acute lymphoblastic leukemia: novel opportunities for drug combinations to overcome resistance. Hantschel O. Haematologica 97 157-159 (2012)
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  18. Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. Woodford MR, Sager RA, Marris E, Dunn DM, Blanden AR, Murphy RL, Rensing N, Shapiro O, Panaretou B, Prodromou C, Loh SN, Gutmann DH, Bourboulia D, Bratslavsky G, Wong M, Mollapour M. EMBO J. 36 3650-3665 (2017)
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  21. EphB4 Regulates Self-Renewal, Proliferation and Neuronal Differentiation of Human Embryonic Neural Stem Cells in Vitro. Liu T, Zeng X, Sun F, Hou H, Guan Y, Guo D, Ai H, Wang W, Zhang G. Cell. Physiol. Biochem. 41 819-834 (2017)
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  31. Abelson Kinases Mediate the Depression of Spontaneous Synaptic Activity Induced by Amyloid Beta 1-42 Peptides. Reichenstein M, Borovok N, Sheinin A, Brider T, Michaelevski I. Cell Mol Neurobiol 41 431-448 (2021)
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  33. E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation. Duan JL, He HQ, Yu Y, Liu T, Ma SJ, Li F, Jiang YS, Lin X, Li DD, Lv QZ, Ma HH, Jia XM. Sci Adv 7 eabe5171 (2021)
  34. Error Tolerance of Machine Learning Algorithms across Contemporary Biological Targets. Kaiser TM, Burger PB. Molecules 24 (2019)
  35. Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility. Bellusci G, Mattiello L, Iannizzotto V, Ciccone S, Maiani E, Villani V, Diederich M, Gonfloni S. Cell Death Dis 10 726 (2019)
  36. MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia. Mazzera L, Abeltino M, Lombardi G, Cantoni AM, Jottini S, Corradi A, Ricca M, Rossetti E, Armando F, Peli A, Ferrari A, Martinelli G, Scupoli MT, Visco C, Bonifacio M, Ripamonti A, Gambacorti-Passerini C, Bonati A, Perris R, Lunghi P. Leukemia (2023)
  37. Neuronal Agrin Promotes Proliferation of Primary Human Myoblasts in an Age-Dependent Manner. Gros K, Matkovič U, Parato G, Miš K, Luin E, Bernareggi A, Sciancalepore M, Marš T, Lorenzon P, Pirkmajer S. Int J Mol Sci 23 11784 (2022)
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  39. Oxidative stress-induced activation of Abl and Src kinases rapidly induces P-glycoprotein internalization via phosphorylation of caveolin-1 on tyrosine-14, decreasing cortisol efflux at the blood-brain barrier. Hoshi Y, Uchida Y, Tachikawa M, Ohtsuki S, Couraud PO, Suzuki T, Terasaki T. J. Cereb. Blood Flow Metab. 271678X18822801 (2019)
  40. Protein Tyrosine Phosphatase Receptor Type J (PTPRJ) Regulates Retinal Axonal Projections by Inhibiting Eph and Abl Kinases in Mice. Yu Y, Shintani T, Takeuchi Y, Shirasawa T, Noda M. J. Neurosci. 38 8345-8363 (2018)
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  42. Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK. Bührmann M, Wiedemann BM, Müller MP, Hardick J, Ecke M, Rauh D. PLoS ONE 12 e0184627 (2017)
  43. The ABL-MYC axis controls WIPI1-enhanced autophagy in lifespan extension. Sporbeck K, Haas ML, Pastor-Maldonado CJ, Schüssele DS, Hunter C, Takacs Z, Diogo de Oliveira AL, Franz-Wachtel M, Charsou C, Pfisterer SG, Gubas A, Haller PK, Knorr RL, Kaulich M, Macek B, Eskelinen EL, Simonsen A, Proikas-Cezanne T. Commun Biol 6 872 (2023)


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