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Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region.

Ahn YM, Clare M, Ensinger CL, Hood MM, Lord JW, Lu WP, Miller DF, Patt WC, Smith BD, Vogeti L, Kaufman MD, Petillo PA, Wise SC, Abendroth J, Chun L, Clark R, Feese M, Kim H, Stewart L, Flynn DL
Bioorg Med Chem Lett 20 5793-8 (2010)
Related entries: 3nnv, 3nnw, 3nnx

Cited: 15 times
EuropePMC logo PMID: 20800479

Abstract

Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.

Articles - 3nnu mentioned but not cited (6)

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  2. p38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma. Yang L, Sun X, Ye Y, Lu Y, Zuo J, Liu W, Elcock A, Zhu S. Front Oncol 9 1294 (2019)
  3. Proteomic profiling change during the early development of silicosis disease. Miao R, Ding B, Zhang Y, Xia Q, Li Y, Zhu B. J Thorac Dis 8 329-341 (2016)
  4. Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology. Da C, Zhang D, Stashko M, Vasileiadi E, Parker RE, Minson KA, Huey MG, Huelse JM, Hunter D, Gilbert TSK, Norris-Drouin J, Miley M, Herring LE, Graves LM, DeRyckere D, Earp HS, Graham DK, Frye SV, Wang X, Kireev D. J Am Chem Soc 141 15700-15709 (2019)
  5. Proteomic profiling differences in serum from silicosis and chronic bronchitis patients: a comparative analysis. Miao R, Ding B, Zhang Y, Xia Q, Li Y, Zhu B. J Thorac Dis 8 439-450 (2016)
  6. Rapid Identification of Inhibitors and Prediction of Ligand Selectivity for Multiple Proteins: Application to Protein Kinases. Ma Z, Huang SY, Cheng F, Zou X. J Phys Chem B 125 2288-2298 (2021)


Reviews citing this publication (3)

  1. Targeted therapy in GIST: in silico modeling for prediction of resistance. Pierotti MA, Tamborini E, Negri T, Pricl S, Pilotti S. Nat Rev Clin Oncol 8 161-170 (2011)
  2. A Comprehensive Structural Overview of p38α Mitogen-Activated Protein Kinase in Complex with ATP-Site and Non-ATP-Site Binders. Astolfi A, Manfroni G, Cecchetti V, Barreca ML. ChemMedChem 13 7-14 (2018)
  3. Molecular mechanisms of drug resistance in tyrosine kinases cAbl and cKit. DiNitto JP, Wu JC. Crit Rev Biochem Mol Biol 46 295-309 (2011)

Articles citing this publication (6)

  1. Natural-product-derived fragments for fragment-based ligand discovery. Over B, Wetzel S, Grütter C, Nakai Y, Renner S, Rauh D, Waldmann H. Nat Chem 5 21-28 (2013)
  2. Structural and evolutionary divergence of eukaryotic protein kinases in Apicomplexa. Talevich E, Mirza A, Kannan N. BMC Evol Biol 11 321 (2011)
  3. Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases. Cowan-Jacob SW, Jahnke W, Knapp S. Future Med Chem 6 541-561 (2014)
  4. Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages. Smith BD, Kaufman MD, Wise SC, Ahn YM, Caldwell TM, Leary CB, Lu WP, Tan G, Vogeti L, Vogeti S, Wilky BA, Davis LE, Sharma M, Ruiz-Soto R, Flynn DL. Mol Cancer Ther 20 2098-2109 (2021)
  5. Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK. Vinh NB, Simpson JS, Scammells PJ, Chalmers DK. J Comput Aided Mol Des 26 409-423 (2012)
  6. Synthesis of piperazine-based thiazolidinones as VEGFR2 tyrosine kinase inhibitors inducing apoptosis. El-Miligy MM, Abd El Razik HA, Abu-Serie MM. Future Med Chem 9 1709-1729 (2017)


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