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Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity.
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Atkinson BN, Willis NJ, Zhao Y, Patel C, Frew S, Costelloe K, Magno L, Svensson F, Jones EY, Fish PV
OpenAccess logo Eur J Med Chem 251 115132 (2023)
Related entries: 8bsp, 8bsq, 8bsr, 8bsz, 8bt0, 8bt2, 8bt5, 8bt7, 8bt8, 8btc, 8bte, 8bth, 8bti

Cited: 3 times
EuropePMC logo PMID: 36934521

Abstract

N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition.

Articles - 8bta mentioned but not cited (1)

  1. Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity. Atkinson BN, Willis NJ, Zhao Y, Patel C, Frew S, Costelloe K, Magno L, Svensson F, Jones EY, Fish PV. Eur J Med Chem 251 115132 (2023)


Articles citing this publication (2)

  1. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Abramson J, Adler J, Dunger J, Evans R, Green T, Pritzel A, Ronneberger O, Willmore L, Ballard AJ, Bambrick J, Bodenstein SW, Evans DA, Hung CC, O'Neill M, Reiman D, Tunyasuvunakool K, Wu Z, Žemgulytė A, Arvaniti E, Beattie C, Bertolli O, Bridgland A, Cherepanov A, Congreve M, Cowen-Rivers AI, Cowie A, Figurnov M, Fuchs FB, Gladman H, Jain R, Khan YA, Low CMR, Perlin K, Potapenko A, Savy P, Singh S, Stecula A, Thillaisundaram A, Tong C, Yakneen S, Zhong ED, Zielinski M, Žídek A, Bapst V, Kohli P, Jaderberg M, Hassabis D, Jumper JM. Nature 630 493-500 (2024)
  2. Upregulation of Fatty Acid Synthase Increases Activity of β-Catenin and Expression of NOTUM to Enhance Stem-like Properties of Colorectal Cancer Cells. Kelson CO, Tessmann JW, Geisen ME, He D, Wang C, Gao T, Evers BM, Zaytseva YY. Cells 13 1663 (2024)


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