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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, 2x2m

Cited: 31 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 - 2x2l mentioned but not cited (3)

  1. Hydrogen bonding penalty upon ligand binding. Zhao H, Huang D. PLoS One 6 e19923 (2011)
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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)

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  12. 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)
  13. 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)
  14. Synthesis, antimicrobial, anticancer, antiviral evaluation and QSAR studies of 4-(1-aryl-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides. Kumar M, Ramasamy K, Mani V, Mishra RK, Majeed ABA, Clercq E, Narasimhan B. Arab J Chem 7 396-408 (2014)
  15. 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)
  16. 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)
  17. 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)
  18. 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)
  19. 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)
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  21. 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)
  22. 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)
  23. 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)
  24. 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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