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2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach.

Schehr M, Ianes C, Weisner J, Heintze L, Müller MP, Pichlo C, Charl J, Brunstein E, Ewert J, Lehr M, Baumann U, Rauh D, Knippschild U, Peifer C, Herges R
Photochem Photobiol Sci 18 1398-1407 (2019)
Related entries: 6hmr, 6hwt, 6hwu, 6hwv

Cited: 24 times
EuropePMC logo PMID: 30924488

Abstract

In photopharmacology, photoswitchable compounds including azobenzene or other diarylazo moieties exhibit bioactivity against a target protein typically in the slender E-configuration, whereas the rather bulky Z-configuration usually is pharmacologically less potent. Herein we report the design, synthesis and photochemical/inhibitory characterization of new photoswitchable kinase inhibitors targeting p38α MAPK and CK1δ. A well characterized inhibitor scaffold was used to attach arylazo- and diazocine moieties. When the isolated isomers, or the photostationary state (PSS) of isomers, were tested in commonly used in vitro kinase assays, however, only small differences in activity were observed. X-ray analyses of ligand-bound p38α MAPK and CK1δ complexes revealed dynamic conformational adaptations of the protein with respect to both isomers. More importantly, irreversible reduction of the azo group to the corresponding hydrazine was observed. Independent experiments revealed that reducing agents such as DTT (dithiothreitol) and GSH (glutathione) that are typically used for protein stabilization in biological assays were responsible. Two further sources of error are the concentration dependence of the E-Z-switching efficiency and artefacts due to incomplete exclusion of light during testing. Our findings may also apply to a number of previously investigated azobenzene-based photoswitchable inhibitors.

Articles - 6hmp mentioned but not cited (3)

  1. A Computational Workflow for the Identification of Novel Fragments Acting as Inhibitors of the Activity of Protein Kinase CK1δ. Bolcato G, Cescon E, Pavan M, Bissaro M, Bassani D, Federico S, Spalluto G, Sturlese M, Moro S. Int J Mol Sci 22 9741 (2021)
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Reviews citing this publication (5)

  1. Photoresponsive molecular tools for emerging applications of light in medicine. Welleman IM, Hoorens MWH, Feringa BL, Boersma HH, Szymański W. Chem Sci 11 11672-11691 (2020)
  2. Molecular photoswitches in aqueous environments. Volarić J, Szymanski W, Simeth NA, Feringa BL. Chem Soc Rev 50 12377-12449 (2021)
  3. Advances and opportunities in the exciting world of azobenzenes. Jerca FA, Jerca VV, Hoogenboom R. Nat Rev Chem 6 51-69 (2022)
  4. Targeted Cancer Therapy Using Compounds Activated by Light. Dunkel P, Ilaš J. Cancers (Basel) 13 3237 (2021)
  5. Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity. Laczi D, Johnstone MD, Fleming CL. Chem Asian J 17 e202200200 (2022)

Articles citing this publication (16)

  1. General Principles for the Design of Visible-Light-Responsive Photoswitches: Tetra-ortho-Chloro-Azobenzenes. Lameijer LN, Budzak S, Simeth NA, Hansen MJ, Feringa BL, Jacquemin D, Szymanski W. Angew Chem Int Ed Engl 59 21663-21670 (2020)
  2. Reversible modulation of circadian time with chronophotopharmacology. Kolarski D, Miró-Vinyals C, Sugiyama A, Srivastava A, Ono D, Nagai Y, Iida M, Itami K, Tama F, Szymanski W, Hirota T, Feringa BL. Nat Commun 12 3164 (2021)
  3. Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib. Heintze L, Schmidt D, Rodat T, Witt L, Ewert J, Kriegs M, Herges R, Peifer C. Int J Mol Sci 21 E8961 (2020)
  4. Structural Aspects of Photopharmacology: Insight into the Binding of Photoswitchable and Photocaged Inhibitors to the Glutamate Transporter Homologue. Arkhipova V, Fu H, Hoorens MWH, Trinco G, Lameijer LN, Marin E, Feringa BL, Poelarends GJ, Szymanski W, Slotboom DJ, Guskov A. J Am Chem Soc 143 1513-1520 (2021)
  5. Controlling the Covalent Reactivity of a Kinase Inhibitor with Light. Reynders M, Chaikuad A, Berger BT, Bauer K, Koch P, Laufer S, Knapp S, Trauner D. Angew Chem Int Ed Engl 60 20178-20183 (2021)
  6. Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines. Liu C, Witt L, Ianes C, Bischof J, Bammert MT, Baier J, Kirschner S, Henne-Bruns D, Xu P, Kornmann M, Peifer C, Knippschild U. Int J Mol Sci 20 E6184 (2019)
  7. Photoswitchable Inhibitor of the Calcium Channel TRPV6. Cunha MR, Bhardwaj R, Lindinger S, Butorac C, Romanin C, Hediger MA, Reymond JL. ACS Med Chem Lett 10 1341-1345 (2019)
  8. Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors. Grathwol CW, Wössner N, Swyter S, Smith AC, Tapavicza E, Hofstetter RK, Bodtke A, Jung M, Link A. Beilstein J Org Chem 15 2170-2183 (2019)
  9. Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors. Kobauri P, Galenkamp NS, Schulte AM, de Vries J, Simeth NA, Maglia G, Thallmair S, Kolarski D, Szymanski W, Feringa BL. J Med Chem 65 4798-4817 (2022)
  10. Active Ester Functionalized Azobenzenes as Versatile Building Blocks. Schultzke S, Walther M, Staubitz A. Molecules 26 3916 (2021)
  11. Light-Controlled Destruction and Assembly: Switching between Two Differently Composed Cage-Type Complexes. Hugenbusch D, Lehr M, von Glasenapp JS, McConnell AJ, Herges R. Angew Chem Int Ed Engl 62 e202212571 (2023)
  12. Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor. Impastato AC, Shemet A, Vepřek NA, Saper G, Hess H, Rao L, Gennerich A, Trauner D. Angew Chem Int Ed Engl 61 e202115846 (2022)
  13. Deactivatable Bisubstrate Inhibitors of Protein Kinases. Sõrmus T, Lavogina D, Enkvist E, Uri A, Viht K. Molecules 27 6689 (2022)
  14. Isomerization of bioactive acylhydrazones triggered by light or thiols. Zhang Z, Le GNT, Ge Y, Tang X, Chen X, Ejim L, Bordeleau E, Wright GD, Burns DC, Tran S, Axerio-Cilies P, Wang YT, Dong M, Woolley GA. Nat Chem 15 1285-1295 (2023)
  15. Light-Control over Casein Kinase 1δ Activity with Photopharmacology: A Clear Case for Arylazopyrazole-Based Inhibitors. Schulte AM, Kolarski D, Sundaram V, Srivastava A, Tama F, Feringa BL, Szymanski W. Int J Mol Sci 23 5326 (2022)
  16. Physicochemical Properties of a Bi-aromatic Heterocyclic-Azo/BSA Hybrid System at the Air-Water Interface. Bal JK, Das N, Mathur T, Plaisier JR, Thomas S. ACS Omega 7 14031-14044 (2022)


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