Biopolym. Cell. 2019; 35(2):143-151.
Bioorganic Chemistry
Hit identification of FGFR1 inhibitors using receptor-based virtual screening
1Tarnavskiy S. S., 1Protopopov M. V., 1Borovykov O. V., 1Pryhodko A. O., 1Bdzhola V. G., 1Yarmoluk S. M.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143

Abstract

Aim. To identify novel FGFR1 inhibitors using the virtual screening approach. Methods. Virtual screening of a small organic compounds library was performed by molecular docking using the Autodock 4.2.6 program package. The compounds activity was determined by in vitro biochemical tests using γ-32P ATP. Results. In vitro experiments demonstrated that 18 compounds belonging to three chemical classes had an inhibitory activity against FGFR1 with IC50 values in the range from 1.8 to 71 μM. Conclusions. Several FGFR1 inhibitors were found using molecular modeling and biochemical testing. These compounds are excellent candidates for further chemical optimization.
Keywords: Fibroblast growth factor receptor 1, molecular docking, virtual screening, in vitro testing

References

[1] Itoh N, Terachi T, Ohta M, Seo MK. The complete amino acid sequence of the shorter form of human basic fibroblast growth factor receptor deduced from its cDNA. Biochem Biophys Res Commun. 1990;169(2):680-5.
[2] 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.
[3] Wu J, Wei T, Tang Q, Weng B, Li W, Jiang X, Ding T, Li X, Liang G, Cai Y, Ji J. Discovery and anti-cancer evaluation of two novel non-ATP-competitive FGFR1 inhibitors in non-small-cell lung cancer. BMC Cancer. 2015;15:276.
[4] Irschick R, Trost T, Karp G, Hausott B, Auer M, Claus P, Klimaschewski L. Sorting of the FGF receptor 1 in a human glioma cell line. Histochem Cell Biol. 2013;139(1):135-48.
[5] Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, Natrajan R, Marchio C, Iorns E, Mackay A, Gillett C, Grigoriadis A, Tutt A, Reis-Filho JS, Ashworth A. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70(5):2085-94.
[6] Yang F, Zhang Y, Ressler SJ, Ittmann MM, Ayala GE, Dang TD, Wang F, Rowley DR. FGFR1 is essential for prostate cancer progression and metastasis. Cancer Res. 2013;73(12):3716-24.
[7] Zhang Y, Guo KJ, Shang H, Wang YJ, Sun LG. Expression of aFGF, bFGF, and FGFR1 in ovarian epithelial neoplasm. Chin Med J (Engl). 2004;117(4):601-3.
[8] 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.
[9] 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.
[10] Gryshchenko 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.
[11] 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
[12] 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.
[13] Grischenko AA, Bdzhola VG, Kukharenko OP, Yarmoluk SM. Search for FGFR1 inhibitors among chromone derivatives. Ukr Bioorg Acta; 2009; 7(1):50-6.
[14] 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.
[15] 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.
[16] 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.
[17] Mukherjee H, Debreczeni J, Breed J, Tentarelli S, Aquila B, Dowling JE, Whitty A, Grimster NP. A study of the reactivity of S((VI))-F containing warheads with nucleophilic amino-acid side chains under physiological conditions. Org Biomol Chem. 2017;15(45):9685-9695.
[18] Beyer H, Schindler W, Leverenz K. Über Thiazole, XXXVII. Chinoide Azomethinfarbstoffe aus Thiazolyl‐(2)‐hydrazin‐Derivaten. Chemische Berichte. 1958;91(11):2438-45.
[19] Hassan KhM, Kamal El-Dean AM, Youssef MSK, Atta FM, Abbady MS. Synthesis and reactions of some thienopyridine derivatives. II Phosphorus, Sulfur Silicon Relat Elem. 1990;47(1-2):181-9.
[20] Wagner G, Vieweg H, Leistner, Boehm SN, Krasselt U, Hanfeld V, Prantz J, Grupe R. ChemInform abstract: synthesis of new primary, secondary, and tertiary 3‐Aminothieno(2,3‐b)pyridine‐2‐carboxamides on different ways. ChemInform. 1990;21(35):102-9.
[21] Shestopalov AM, Promonenkov VK, Sharanin YuA, et al. Cyclization of nitriles. Syntheses and reactions of 3-amino-2-carboxamide-thieno[2,3-b]pyridines. J Org Chem USSR. 1984;20(7):1382
[22] Byrd CM, Dai Dongchen, Jordan Robert. Hruby Dennis. Thienepiridines derivatives for the treatment and prevention of dengue virus infections. WO2010/99166, 2010,A1.
[23] Tarnavsky SS, Dubinina GG, Yarmoluk SM, Golovach SM. Interaction 3,4-dichloromaleimides with N- and S-nucleofiles. Ukr Khim Zh. 2002;68(9):47-51.
[24] Tarnavsky SS, Dubinina GG, Golovach SM, Yarmoluk SM. Antitumor activity among derivatives of the 3-chloro-4-(3-hydroxyanilino) -2,5-dihydropyrrole-2,5-dione. Biopolym Cell. 2003;19(6):548-52.