Biopolym. Cell. 2019; 35(2):152-162.
Биоорганическая химия
Идентификация ингибиторов FGFR1 среди 4-метокситиено[2,3‐d]пиримидинов.
1Котей И. М., 1Протопопов Н. В., 1Старосила С. А., 1Плетнёва Л. В., 1Приходько А. А., 1Баланда А. А., 1Бджола В. Г., 1Ярмолюк С. М.
  1. Институт молекулярной биологии и генетики НАН Украины
    ул. Академика Заболотного, 150, Киев, Украина, 03143

Abstract

Цель. Поиск новых химических соединений со способностью ингибировать протеинкиназу FGFR1. Методы. В работе использовались методы органического синтеза, молекулярного докинга программным пакетом Autodock 4.2.6 и биохимическое тестирование in vitro, используя γ-32P ATФ. Результаты. Биохимическое тестирование показало, что 9 из 23 исследуемых соединений ингибируют протеинкиназу FGFR1 в диапазоне значений IC50 от 0.9 до 5.6 μМ. Выводы. Было разработано девять ингибиторов FGFR1. С помощью молекулярного докинга было определено положение лигандов в АТФ-акцепторном сайте и изучено зависимость активности от структуры заместителей R1, R4 та R5.
Keywords: Протеинкиназа FGFR1, молекулярный докинг, органический синтез, in vitro тестирование, 4-метокситиено[2,3‐d]пиримидин

References

[1] Yu T, Yang Y, Liu Y, Zhang Y, Xu H, Li M, Ponnusamy M, Wang K, Wang JX, Li PF. A FGFR1 inhibitor patent review: progress since 2010. Expert Opin Ther Pat. 2017;27(4):439-454.
[2] Chioni AM, Grose R. FGFR1 cleavage and nuclear translocation regulates breast cancer cell behavior. J Cell Biol. 2012;197(6):801-17.
[3] Weiss J, Sos ML, Seidel D, Peifer M, Zander T, Heuckmann JM, Ullrich RT, Menon R, Maier S, Soltermann A, Moch H, Wagener P, Fischer F, Heynck S, Koker M, Schöttle J, Leenders F, Gabler F, Dabow I, Querings S, Heukamp LC, Balke-Want H, Ansén S, Rauh D, Baessmann I, Altmüller J, Wainer Z, Conron M, Wright G, Russell P, Solomon B, Brambilla E, Brambilla C, Lorimier P, Sollberg S, Brustugun OT, Engel-Riedel W, Ludwig C, Petersen I, Sänger J, Clement J, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman D, Cappuzzo F, Ligorio C, Damiani S, Hallek M, Beroukhim R, Pao W, Klebl B, Baumann M, Buettner R, Ernestus K, Stoelben E, Wolf J, Nürnberg P, Perner S, Thomas RK. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med. 2010;2(62):62ra93.
[4] Sahores A, May M, Sequeira GR, Fuentes C, Jacobsen B, Lanari C, Lamb CA. Targeting FGFR with BGJ398 in Breast Cancer: Effect on Tumor Growth and Metastasis. Curr Cancer Drug Targets. 2018;18(10):979-987.
[5] Gryshchenko AA, Levchenko KV, Bdzhola VG, Ruban TP, Lukash LL, Yarmoluk SM. Design, synthesis and biological evaluation of naphthostyril derivatives as novel protein kinase FGFR1 inhibitors. J Enzyme Inhib Med Chem. 2015;30(1):126-32.
[6] Gryshchenko AA, Bdzhola VG, Balanda AO, Briukhovetska NV, Kotey IM, Golub AG, Ruban TP, Lukash LL, Yarmoluk SM. Design, synthesis and biological evaluation of N-phenylthieno[2,3-d]pyrimidin-4-amines as inhibitors of FGFR1. Bioorg Med Chem. 2015;23(9):2287-93.
[7] GGryshchenko AA, Bdzhola VG, Pletnyova LV, Chepurna RV, Zhitnetsky IV, Yarmoluk SM. Quinazolone inhibitors of protein kinase FGFR1. Ukr Bioorg Acta 2010; 8(2):63-8.
[8] Gryshchenko AA, Bdzhola VG, Borovikov OV, Kukharenko OP, Pletnyova LV, Yarmoluk SM. Search for FGFR1 inhibitors among oxindole derivatives. Ukr Bioorg Acta; 2009; 7(2):64-8
[9] Gryshchenko AA, Tarnavskiy SS, Levchenko KV, Bdzhola VG, Volynets GP, Golub AG, Ruban TP, Vygranenko KV, Lukash LL, Yarmoluk SM. Design, synthesis and biological evaluation of 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones as inhibitors of protein kinase FGFR1. Bioorg Med Chem. 2016;24(9):2053-9.
[10] Grischenko AA, Bdzhola VG, Kukharenko OP, Yarmoluk SM. Search for FGFR1 inhibitors among chromone derivatives. Ukr Bioorg Acta; 2009; 7(1):50-6.
[11] Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-91.
[12] Pedretti A, Villa L, Vistoli G. VEGA--an open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming. J Comput Aided Mol Des. 2004;18(3):167-73.
[13] Syniugin AR, Ostrynska OV, Chekanov MO, Volynets GP, Starosyla SA, Bdzhola VG, Yarmoluk SM. Design, synthesis and evaluation of 3-quinoline carboxylic acids as new inhibitors of protein kinase CK2. J Enzyme Inhib Med Chem. 2016;31(sup4):160-9.
[14] Bae JH, Lew ED, Yuzawa S, Tomé F, Lax I, Schlessinger J. The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site. Cell. 2009;138(3):514-24.
[15] Sabnis RW, Rangnekar DW, Sonawane ND. 2-aminothiophenes by the gewald reaction. J Heterocycl Chem. 1999;36(2):333–45. ttps://
[16] Golub AG, Bdzhola VG, Briukhovetska NV, Balanda AO, Kukharenko OP, Kotey IM, Ostrynska OV, Yarmoluk SM. Synthesis and biological evaluation of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids as inhibitors of human protein kinase CK2. Eur J Med Chem. 2011;46(3):870-6.
[17] Ostrynska OV, Balanda AO, Bdzhola VG, Golub AG, Kotey IM, Kukharenko OP, Gryshchenko AA, Briukhovetska NV, Yarmoluk SM. Design and synthesis of novel protein kinase CK2 inhibitors on the base of 4-aminothieno[2,3-d]pyrimidines. Eur J Med Chem. 2016;115:148-60.