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Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor.

Shraga A, Olshvang E, Davidzohn N, Khoshkenar P, Germain N, Shurrush K, Carvalho S, Avram L, Albeck S, Unger T, Lefker B, Subramanyam C, Hudkins RL, Mitchell A, Shulman Z, Kinoshita T, London N
Cell Chem Biol 26 98-108.e5 (2019)
Cited: 22 times
EuropePMC logo PMID: 30449673

Abstract

The c-Jun NH2-terminal kinase (JNK) signaling pathway is central to the cell response to stress, inflammatory signals, and toxins. While selective inhibitors are known for JNKs and for various upstream MAP3Ks, no selective inhibitor is reported for MKK7--one of two direct MAP2Ks that activate JNK. Here, using covalent virtual screening, we identify selective MKK7 covalent inhibitors. We optimized these compounds to low-micromolar inhibitors of JNK phosphorylation in cells. The crystal structure of a lead compound bound to MKK7 demonstrated that the binding mode was correctly predicted by docking. We asserted the selectivity of our inhibitors on a proteomic level and against a panel of 76 kinases, and validated an on-target effect using knockout cell lines. Lastly, we show that the inhibitors block activation of primary mouse B cells by lipopolysaccharide. These MKK7 tool compounds will enable better investigation of JNK signaling and may serve as starting points for therapeutics.

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Reviews citing this publication (7)

  1. Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation. Zhang T, Hatcher JM, Teng M, Gray NS, Kostic M. Cell Chem Biol 26 1486-1500 (2019)
  2. Advances in covalent drug discovery. Boike L, Henning NJ, Nomura DK. Nat Rev Drug Discov 21 881-898 (2022)
  3. MKK7, the essential regulator of JNK signaling involved in cancer cell survival: a newly emerging anticancer therapeutic target. Park JG, Aziz N, Cho JY. Ther Adv Med Oncol 11 1758835919875574 (2019)
  4. Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery. Li Q, Kang C. Int J Mol Sci 21 E5262 (2020)
  5. Non-'classical' MEKs: A review of MEK3-7 inhibitors. Kwong AJ, Scheidt KA. Bioorg Med Chem Lett 30 127203 (2020)
  6. Docking covalent targets for drug discovery: stimulating the computer-aided drug design community of possible pitfalls and erroneous practices. Oyedele AK, Ogunlana AT, Boyenle ID, Adeyemi AO, Rita TO, Adelusi TI, Abdul-Hammed M, Elegbeleye OE, Odunitan TT. Mol Divers 27 1879-1903 (2023)
  7. Technologies for Direct Detection of Covalent Protein-Drug Adducts. Mons E, Kim RQ, Mulder MPC. Pharmaceuticals (Basel) 16 547 (2023)

Articles citing this publication (14)

  1. Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening. Resnick E, Bradley A, Gan J, Douangamath A, Krojer T, Sethi R, Geurink PP, Aimon A, Amitai G, Bellini D, Bennett J, Fairhead M, Fedorov O, Gabizon R, Gan J, Guo J, Plotnikov A, Reznik N, Ruda GF, Díaz-Sáez L, Straub VM, Straub VM, Szommer T, Velupillai S, Zaidman D, Zhang Y, Coker AR, Dowson CG, Barr HM, Wang C, Huber KVM, Brennan PE, Ovaa H, von Delft F, London N. J Am Chem Soc 141 8951-8968 (2019)
  2. An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor. Zaidman D, Gehrtz P, Filep M, Fearon D, Gabizon R, Douangamath A, Prilusky J, Duberstein S, Cohen G, Owen CD, Resnick E, Strain-Damerell C, Lukacik P, Covid-Moonshot Consortium, Barr H, Walsh MA, von Delft F, London N. Cell Chem Biol 28 1795-1806.e5 (2021)
  3. 10 years into the resurgence of covalent drugs. De Vita E. Future Med Chem 13 193-210 (2021)
  4. Merits and pitfalls of conventional and covalent docking in identifying new hydroxyl aryl aldehyde like compounds as human IRE1 inhibitors. Carlesso A, Chintha C, Gorman AM, Samali A, Eriksson LA. Sci Rep 9 3407 (2019)
  5. Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis. Yan Y, Zhou B, Qian C, Vasquez A, Kamra M, Chatterjee A, Lee YJ, Yuan X, Ellis L, Di Vizio D, Posadas EM, Kyprianou N, Knudsen BS, Shah K, Murali R, Gertych A, You S, Freeman MR, Yang W. Nat Commun 13 669 (2022)
  6. Insights into the Interaction Mechanism of DTP3 with MKK7 by Using STD-NMR and Computational Approaches. Sandomenico A, Di Rienzo L, Calvanese L, Iaccarino E, D'Auria G, Falcigno L, Chambery A, Russo R, Franzoso G, Tornatore L, D'Abramo M, Ruvo M, Milanetti E, Raimondo D. Biomedicines 9 20 (2020)
  7. Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK. Forster M, Liang XJ, Schröder M, Gerstenecker S, Chaikuad A, Knapp S, Laufer S, Gehringer M. Int J Mol Sci 21 E9269 (2020)
  8. Synthesis, anticancer activity, and molecular modeling of 1,4-naphthoquinones that inhibit MKK7 and Cdc25. Schepetkin IA, Karpenko AS, Khlebnikov AI, Shibinska MO, Levandovskiy IA, Kirpotina LN, Danilenko NV, Quinn MT. Eur J Med Chem 183 111719 (2019)
  9. Optimization of Covalent MKK7 Inhibitors via Crude Nanomole-Scale Libraries. Gehrtz P, Marom S, Bührmann M, Hardick J, Kleinbölting S, Shraga A, Dubiella C, Gabizon R, Wiese JN, Müller MP, Cohen G, Babaev I, Shurrush K, Avram L, Resnick E, Barr H, Rauh D, London N. J Med Chem 65 10341-10356 (2022)
  10. A simple method for developing lysine targeted covalent protein reagents. Gabizon R, Tivon B, Reddi RN, van den Oetelaar MCM, Amartely H, Cossar PJ, Ottmann C, London N. Nat Commun 14 7933 (2023)
  11. Components of the JNK-MAPK pathway play distinct roles in hepatocellular carcinoma. Yu J, Li X, Cao J, Zhu T, Liang S, Du L, Cao M, Wang H, Zhang Y, Zhou Y, Shen B, Feng J, Zhang J, Wang J, Jin J. J Cancer Res Clin Oncol 149 17495-17509 (2023)
  12. Letter Covalent docking in CDOCKER. Wu Y, Brooks Iii CL. J Comput Aided Mol Des 36 563-574 (2022)
  13. Rapid signaling reactivation after targeted BRAF inhibition predicts the proliferation of individual melanoma cells from an isogenic population. Khoshkenar P, Lowry E, Mitchell A. Sci Rep 11 15473 (2021)
  14. Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors. Kim DR, Orr MJ, Kwong AJ, Deibler KK, Munshi HH, Bridges CS, Chen TJ, Zhang X, Lacorazza HD, Scheidt KA. ACS Med Chem Lett 14 606-613 (2023)


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