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Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.

Mologni L, Rostagno R, Brussolo S, Knowles PP, Kjaer S, Murray-Rust J, Rosso E, Zambon A, Scapozza L, McDonald NQ, Lucchini V, Gambacorti-Passerini C
Bioorg Med Chem 18 1482-96 (2010)
Related entries: 2x2k, 2x2l

Cited: 27 times
EuropePMC logo PMID: 20117004

Abstract

The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers.

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Articles - 2x2m mentioned but not cited (1)

  1. Identification of potential biological targets of oxindole scaffolds via in silico repositioning strategies. Tinivella A, Pinzi L, Gambacorta G, Baxendale I, Rastelli G. F1000Res 11 Chem Inf Sci-217 (2022)


Reviews citing this publication (3)

  1. Mechanisms of RET signaling in cancer: current and future implications for targeted therapy. Plaza-Menacho I, Mologni L, McDonald NQ. Cell Signal 26 1743-1752 (2014)
  2. Analysis of the regulatory and catalytic domains of PTEN-induced kinase-1 (PINK1). Sim CH, Gabriel K, Mills RD, Culvenor JG, Cheng HC. Hum Mutat 33 1408-1422 (2012)
  3. RET kinase inhibitors: a review of recent patents (2012-2015). Mologni L, Gambacorti-Passerini C, Goekjian P, Scapozza L. Expert Opin Ther Pat 27 91-99 (2017)

Articles citing this publication (22)

  1. The methionine-aromatic motif plays a unique role in stabilizing protein structure. Valley CC, Cembran A, Perlmutter JD, Lewis AK, Labello NP, Gao J, Sachs JN. J Biol Chem 287 34979-34991 (2012)
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  3. Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans. Plaza-Menacho I, Barnouin K, Goodman K, Martínez-Torres RJ, Borg A, Murray-Rust J, Mouilleron S, Knowles P, McDonald NQ. Mol Cell 53 738-751 (2014)
  4. Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents. Eldehna WM, Altoukhy A, Mahrous H, Abdel-Aziz HA. Eur J Med Chem 90 684-694 (2015)
  5. Design, synthesis and biological evaluation of novel 4-thiazolidinones containing indolin-2-one moiety as potential antitumor agent. Wang S, Zhao Y, Zhang G, Lv Y, Zhang N, Gong P. Eur J Med Chem 46 3509-3518 (2011)
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  10. Substituted indolin-2-ones as p90 ribosomal S6 protein kinase 2 (RSK2) inhibitors: Molecular docking simulation and structure-activity relationship analysis. Zhong Y, Xue M, Zhao X, Yuan J, Liu X, Huang J, Zhao Z, Li H, Xu Y. Bioorg Med Chem 21 1724-1734 (2013)
  11. Regioselective synthesis of 2-(bromomethyl)-5-aryl-thiophene derivatives via palladium (0) catalyzed suzuki cross-coupling reactions: as antithrombotic and haemolytically active molecules. Rizwan K, Zubair M, Rasool N, Ali S, Zahoor AF, Rana UA, Khan SU, Shahid M, Zia-Ul-Haq M, Jaafar HZ. Chem Cent J 8 74 (2014)
  12. Selective C-arylation of 2,5-dibromo-3-hexylthiophene via Suzuki cross coupling reaction and their pharmacological aspects. Ikram HM, Rasool N, Ahmad G, Chotana GA, Musharraf SG, Zubair M, Rana UA, Zia-Ul-Haq M, Jaafar HZ. Molecules 20 5202-5214 (2015)
  13. Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation. Li Y, Nam K. Chem Sci 8 3453-3464 (2017)
  14. Design, synthesis and biological evaluation of 3-substituted-2-oxindole hybrid derivatives as novel anticancer agents. Romagnoli R, Baraldi PG, Prencipe F, Oliva P, Baraldi S, Salvador MK, Lopez-Cara LC, Bortolozzi R, Mattiuzzo E, Basso G, Viola G. Eur J Med Chem 134 258-270 (2017)
  15. Discovery of di-indolinone as a novel scaffold for protein tyrosine phosphatase 1B inhibitors. Dai HL, Gao LX, Yang Y, Li JY, Cheng JG, Li J, Wen R, Peng YQ, Zheng JB. Bioorg Med Chem Lett 22 7440-7443 (2012)
  16. Characterization of LDD-2633 as a Novel RET Kinase Inhibitor with Anti-Tumor Effects in Thyroid Cancer. Lee HJ, Jeong P, Moon Y, Choi J, Heo JD, Kim YC, Han SY. Pharmaceuticals (Basel) 14 38 (2021)
  17. Design, Synthesis and Preliminary Biological Evaluation of Novel Benzyl Sulfoxide 2-Indolinone Derivatives as Anticancer Agents. Tang L, Peng T, Wang G, Wen X, Sun Y, Zhang S, Liu S, Wang L. Molecules 22 E1979 (2017)
  18. Synthesis and biological evaluation of 2-(5-substituted-1-((diethylamino)methyl)-2-oxoindolin-3-ylidene)-N-substituted-hydrazinecarbothioamides. Karki SS, Kulkarni AA, Kumar S, Veliyath SK, De Clercq E, Balzarini J. Med Chem Res 22 2014-2022 (2013)
  19. Synthesis of a new class of antimicrobial agents incorporating the indolin-2-one moiety. Kandile NG, Zaky HT, Saleh YG, Ahmed NA. J Enzyme Inhib Med Chem 28 853-862 (2013)
  20. The interaction of 4-thiazolidinone derivatives containing indolin-2-one moiety with P-glycoprotein studied using K562 cell lines. Wang F, Liu Z, Wang J, Tao J, Gong P, Bao X, Zhao Y, Wang Y. Eur J Med Chem 101 126-132 (2015)
  21. Synthesis, Biological, and Computational Evaluation of Novel 1,3,5-Substituted Indolin-2-one Derivatives as Inhibitors of Src Tyrosine Kinase. Kilic-Kurt Z, Bakar F, Ölgen S. Arch Pharm (Weinheim) 348 715-729 (2015)
  22. Design and Synthesis of Novel Thieno[3,2-c]quinoline Compounds with Antiproliferative Activity on RET-Dependent Medullary Thyroid Cancer Cells. La Monica G, Pizzolanti G, Baiamonte C, Bono A, Alamia F, Mingoia F, Lauria A, Martorana A. ACS Omega 8 34640-34649 (2023)


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