Stručný pohľad na vlastnosti in silico, vzťahy štruktúra– –aktivita a biotransformáciu fruquintinibu, protinádorovo účinkujúceho liečiva novej generácie obsahujúceho privilegované benzofuránové zoskupenie

Download PDF English version

Authors: Dominika Nádaská ¹; Lucia Hudecova ²; Gustáv Kováč ²; Ivan Malík ^1,2
Authors‘ workplace: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University Bratislava, Slovak Republic ¹; Institute of Chemistry, Clinical Biochemistry and Laboratory Medicine Faculty of Medicine, Slovak Medical University in Bratislava, Slovak Republic ²
Published in: Čes. slov. Farm., 2023; 72, 267-276
Category: Review Articles
doi: https://doi.org/10.5817/CSF2023-6-267

Overview

Súčasné trendy projekcie liečiv významne reflektujú tzv. privilegované zoskupenia ako základné (tzv. jadrové) štruktúrne fragmenty s rozhodujúcim vplyvom na afinitu k vhodne zvoleným biologickým cieľom, účinok, selektivitu aj toxikologické charakteristiky týchto liečiv a perspektívnych kandidátov na liečivá. Fruquintinib (1) je nový syntetický selektívny inhibítor izoforiem receptora vaskulárneho endotelového rastového faktora (z angl. vascular endothelial growth factor receptor; VEGFR), t. j. VEGFR-1, VEGFR-2 a VEGFR-3. Terapeutikum (1) obsahuje planárne bicyklické heteroaromatické jadro, v ktorom sú vhodne inkorporované dva atómy dusíka, základný (jadrový) bicyklický heteroaromatický kruh – privilegované (substituované) benzofuránové zoskupenie a skupinu pôsobiacu ako donor a akceptor väzby vodíkovým mostíkom (VVM), t. j. amidové funkčné zoskupenie. Fruquintinib (1) bol prvýkrát schválený v Číne pre liečbu metastázujúceho kolorektálneho karcinómu, závažného nádorového ochorenia s vysokou mortalitou. Táto prehľadová publikácia ponúkla stručný pohľad na tému privilegovaných štruktúr, ich niekoľkých parametrov, ktorých rozsah približuje tzv. liečivu podobné (drug-like) vlastnosti, farmakodynamické charakteristiky fruquintinibu (1) a rôzne in silico-deskriptory definujúce štruktúrne a fyzikálno-chemické vlastnosti tohto liečiva (molekulová hmotnosť, počet ťažkých atómov, počet aromatických tažkých atómov, frakcia C-atómov v sp3-hybridizovanom stave, počet akceptorov VVM, počet donorov VVM, celkový polárny povrch, molekulová refrakcia, molekulový objem aj parametre lipofility a rozpustnosti). Niektoré z týchto deskriptorov súviseli s farmakokinetikou aj distribúciou fruquintinibu (1) a navyše by mohli pomôcť predikovať jeho schopnosť pasívne prechádzať hematoencefalickou bariérou (HEB). V publikácii sa hodnotila aj eventuálna súvislosť medzi indukčným potenciálom liečiva (1) voči izoenzýmom cytochrómu P450 (CYP1A2 a CYP3A4) a jeho pasívnym transportom do centrálneho nervového systému via HEB. Stručne boli takisto načrtnuté súčasné klinické skúsenosti s fruquintinibom (1) a budúce liečebné možnosti tohto terapeutika.

Klíčová slova:

privilegované zoskupenie – fruquinti- nib – vlastnosti in silico – vzťahy štuktúra–aktivita – far- makokinetika

Sources

Zhao H., Dietrich J. Privileged scaffolds in lead generation. Expert Opin. Drug. Discov. 2015; 10, 781–790. doi:10.1517/17460441.2015.1041496
Evans B. E., Rittle K. E., Bock M. G., DiPardo R. M., Freidinger R. M., Whitter W. L., Lundell G. F., Veber D. F., Anderson P. S., Chang R. S. L., Lotti V. J., Cerino D. J., Chen T. B., Kling P. J., Kunkel K. A., Springer J. P., Hirshfield J. Methods for drug discovery: development of potent,selective, orally effective cholecystin antagonists. J. Med. Chem. 1988; 31, 2235–2246. doi: 10.1021/ jm00120a002
Kourounakis A. P., Xanthopoulos D., Tzara A. Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules. Med. Res. Rev. 2020; 40, 709–752. doi: 10.1002/med.21634
Datusalia A. K., Khatik G. L. Thiazole heterocycle: A privileged scaffold for drug design and discovery. Curr. Drug Discov. Technol.2018; 15, 162. doi: 10.2174/157016381503180620153423
Gharat R., Prabhu A., Khambete M. P. Potential of triazines in Alzheimer’s disease: A versatile privileged scaffold. Arch. Pharm. (Weinheim) 2022; 355, art. no. e2100388 (12 pp.). doi: 10.1002/ardp.202100388
Maclean D., Baldwin J. J., Ivanov V. T., Kato Y., Shaw A., Schenider P., Gordon E. M. Glossary of terms used in combinatorial chemistry (technical report). J. Comb. Chem. 2000; 2, 562–578. doi: 10.1021/cc000071u
Horton D. A., Bourne G. T., Smythe M. L. The combinatorial synthesis of bicyclic privileged structures or privileged substructures.Chem. Rev. 2003; 103, 893–930. doi: 10.1021/cr020033s
Costantino L., Barlocco D. Privileged structures as leads in medicinal chemistry. Curr. Med. Chem. 2006; 13, 6585. doi: 10.2174/092986706775197999
Rusinov V. L., Charushin V. N., Chupakhin O. N. Biologically active azolo-1,2,4-triazines and azolopyrimidines. Russ. Chem. Bull. 2018; 67, 573–599. doi: 10.1007/ s11172-018-2113-8
Voinkov E. K., Drokin R. A., Fedotov V. V., Butorin I. I., Savateev K. V., Lyapustin D. N., Gazizov D. A., Gorbunov E. B., Slepukhin P. A., Gerasimova N. A., Evstigneeva N. P., Zilberberg N. V., Kungurov N. V., Ulomsky E. N., Rusinov V. L. Azolo[5,1-c][1,2,4]triazines and azoloazapurines: Synthesis, antimicrobial activity and in silico studies. ChemistrySelect 2022; 7, art. no. e202104253 (8 pp.). doi: 10.1002/slct.202104253
Savateev K. V., Ulomsky E. N., Butorin I. I., Charushin V. N., Rusinov V. L., Chupakhin O. N. Azoloazines as A2a receptor antagonists.Structure–activity relationship. Russ. Chem. Rev. 2018; 87, 636–669. doi: 10.1070/RCR4792
Han Ch., Zhang J., Zheng M., Xiao Y., Li Y., Liu G. An integrated drug-likeness study for bicyclic privileged structures: from physicochemical properties to in vitro ADME properties. Mol. Divers. 2011; 15, 857–876. doi: 10.1007/s11030-011-9317-2
Hubatsch I., Ragnarsson E. G. E., Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat. Protoc. 2007; 2, 2111–2119. doi: 10.1038/nprot.2007.303
Jakopin Ž. 2-Aminothiazoles in drug discovery: Privileged structures or toxicophores? Chem. Biol. Interact. 2020; 330, art. no. 109244 (8 pp.). doi: 10.1016/j. cbi.2020.109244
Atmaram U. A., Roopan S. M. Biological activity of oxadiazole and thiadiazole derivatives. Appl. Microbiol. Biotechnol. 2022; 106, 3489–3505. doi: 10.1007/s00253-022-11969-0
He M., Fan M., Peng Z., Wang G. An overview of hydroxypyranone and hydroxypyridinone as privileged scaffolds for novel drug discovery. Eur. J. Med. Chem. 2021; 221, art. no. 113546 (29 pp.). doi: 10.1016/j.ejmech.2021.113546
Rakesh K. P., Shantharam C. S., Sridhara M. B., Manukumar H. M., Qin H.-L. Benzisoxazole: a privileged scaffold for medicinal chemistry. Med. Chem. Commun. 2017; 8, 2023–2039. doi: 10.1039/c7md00449d
Saroha B., Kumar G., Kumari M., Kaur R., Raghav N., Sharma P. K., Kumar N., Kumar S. A decennary update on diverse heterocycles and their intermediates as privileged scaffolds for cathepsin B inhibition. Int. J. Biol. Macromol. 2022; 222 (Part B),2270–2308. doi: 10.1016/j. ijbiomac.2022.10.017
Avula S. K., Das B., Csuk R., Al-Harrasi A. Naturally occurring O-heterocycles as anticancer agents. Anticancer Agents Med.Chem. 2022; 22, 3208–3218. doi: 10.2174/1871520621666211108091444
Pairas G. N., Perperopoulou F., Tsoungas P. G., Varvounis G. The isoxazole ring and its N-oxide: A privileged core structure in neuropsychiatric therapeutics. ChemMedChem. 2017; 12, 408–419. doi: 10.1002/ cmdc.201700023
Wang Xi., Wang Xu., Zhao Y., Zhang X. Two previously undescribed benzofuran derivatives from the flowers of Callistephuschinensis. Phytochem. Lett. 2022; 51, 145–148. doi: 10.1016/j.phytol.2022.08.012
Abu-Hashem A. A., Hussein H. A. R., Aly A. S., Gouda M. A. Reactivity of benzofuran derivatives. Synth. Commun. 2014; 44, 2899–2920. doi: 10.1080/00397911.2014.907425
Abbas A. A., Dawood K. M. Anticancer therapeutic potential of benzofuran scaffolds. RSC Adv. 2023; 13, 11096–11120. doi: 10.1039/d3ra01383a
Fuloria Sh., Sekar M., Khattulanuar F. S., Gan S. H., Rani N. N. I. M., Ravi S., Subramaniyan V., Jeyabalan S., Begum M. Y., Chidambaram K., Sathasivam K. V., Safi Sh. Z., Wu Y. S., Nordin R., Maziz M. N. H., Kumarasamy V., Lum P. T., Fuloria N. K.Chemistry, biosynthesis and pharmacology of viniferin: Potential resveratrol-derived molecules for new drug discovery, development and therapy. Molecules 2022; 27, art. no. 5072 (33 pp.). doi: 10.3390/molecules27165072
Khanam H., Shamsuzzaman. Bioactive benzofuran derivatives: A review. Eur. J. Med. Chem. 2015; 97, 483–504. doi:10.1016/j.ejmech.2014.11.039
Chiummiento L., D’Orsi R., Funicello M., Lupattelli P. Last decade of unconventional methodologies for the synthesis of substituted benzofurans. Molecules 2020; 25, art. no. 2327 (52 pp.). doi: 10.3390/molecules25102327
Modell A. E., Blosser S. L., Arora P. S. Systematic targeting of protein–protein interactions. Trends Pharmacol. Sci. 2016; 37, 702–713. doi: 10.1016/j.tips.2016.05.008
Farhat J., Alzyoud L., Alwahsh M., Al-Omari B. Structure–activity relationship of benzofuran derivatives with potential anticancer activity. Cancers (Basel) 2022; 14, art. no. 2196 (22 pp.). doi: 10.3390/cancers14092196
Dawood K. M. Benzofuran derivatives: a patent review. Expert Opin. Ther. Pat. 2013; 23, 1133–1156. doi:10.1517/13543776.2013.801455
Xu Zh., Zhao Sh., Lv Z., Feng L., Wang Y., Zhang F., Bai L., Deng J. Benzofuran derivatives and their anti-tubercular, antibacterial activities. Eur. J. Med. Chem. 2019; 162, 266–276. doi: 10.1016/j.ejmech.2018.11.025
Nevagi R. J., Dighe S. N., Dighe S. N. Biological and medicinal significance of benzofuran. Eur. J. Med. Chem. 2015; 97, 561–581. doi: 10.1016/j.ejmech.2014.10.085
Ahmad A., Nawaz M. I. Molecular mechanism of VEGF and its role in pathological angiogenesis. J. Cell. Biochem. 2022; 123, 1938–1965. doi: 10.1002/jcb.30344
Malekan M., Ebrahimzadeh M. A. Vascular endothelial growth factor receptors [VEGFR] as target in breast cancer treatment: Current status in preclinical and clinical studies and future directions. Curr. Top. Med. Chem. 2022; 22, 891–920. doi: 10.2174/1568026622666220308161710
Olsson A.-K., Dimberg A., Kreuger J., Claesson-Welsh L. VEGF receptor signalling – in control of vascular function. Nat. Rev. Mol. Cell Biol. 2006; 7, 359–371. doi: 10.1038/nrm1911
Mabeta P., Steenkamp V. The VEGF/VEGFR axis revisited: Implications for cancer therapy. Int. J. Mol. Sci. 2022; 23, art. no. 15585 (14 pp.). doi: 10.3390/ijms232415585
Zhang Y., Zou J.-Y., Wang Zh., Wang Y. Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. Cancer Manag. Res. 2019; 11, 7787–7803. doi: 10.2147/CMAR.S215533
Li X., Zhou J., Wang X., Li Ch., Ma Z., Wan Q., Peng F. New advances in the research of clinical treatment and novel anticanceragents in tumor angiogenesis. Biomed. Pharmacother. 2023; 163, art. no. 114806 (16 pp.). doi: 10.1016/j.biopha.2023.114806
Sun Q., Zhou J., Zhang Zh., Guo M., Liang J., Zhou F., Long J., Zhang W., Yin F., Cai H., Yang H., Zhang W., Gu Y., Ni L., Sai Y., Cui Y., Zhang M., Hong M., Sun J., Yang Zh., Qing W., Su W., Ren Y. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol. Ther. 2014; 15, 1635–1645. doi:10.4161/15384047.2014.964087
Chen Zh., Jiang L. The clinical application of fruquintinib on colorectal cancer. Expert Rev. Clin. Pharmacol. 2019; 12, 713–721. doi:10.1080/17512433.2019.1630272
Shirley M. Fruquintinib: First global approval. Drugs 2018; 78, 1757–1761. doi: 10.1007/s40265-018-0998-z
Lavacchi D., Roviello G., Guidolin A., Romano S., Venturini J., Caliman E., Vannini A., Giommoni E., Pellegrini E., Brugia M., Pillozzi S., Antonuzzo L. Evaluation of fruquintinib in the continuum of care of patients with colorectal cancer. Int. J. Mol. Sci. 2023; 24, art. no. 5840 (12 pp.). doi: 10.3390/ijms24065840
Modi S. J., Kulkarni V. K. Exploration of structural requirements for the inhibition of VEGFR-2 tyrosine kinase: Binding site analysis of type II, ’DFG-out’ inhibitors. J. Biomol. Struct. Dyn. 2022; 40, 5712–5727. doi: 10.1080/07391102.2021.1872417
Daina A., Michielin O., Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017; 7, art. no. 42717 (13 pp.). doi: 10.1038/ srep42717
Moriguchi I., Hirono Sh., Liu Q., Nakagome I., Matsushita Y. Simple method of calculating octanol / water partition coefficient.Chem. Pharm. Bull. 1992; 40, 127–130. doi: 10.1248/cpb.40.127
Moriguchi I., Hirono Sh., Nakagome I., Hirano H. Comparison of reliability of log P values for drugs calculated by several methods. Chem. Pharm. Bull. 1994; 42, 976–978. doi: 10.1248/cpb.42.976
Lipinski Ch. A., Lombardo F., Dominy D. W., Feeney P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001; 46, 3–26. doi: 10.1016/s0169-409x(00)00129-0
PerkinElmer. https://www.perkinelmer.com/analytical-and-enterprise-solutions.html (accessed on: September 24, 2023)
Molinspiration Cheminformatics. https://www.molinspiration.com/cgi-bin/properties (accessed on: September 24, 2023)
Ali J., Camilleri P., Brown M. B., Hutt A. J., Kirton S. B. In silico prediction of aqueous solubility using simple QSPR models: theimportance of phenol and phenol-like moieties. J. Chem. Inf. Model. 2012; 52, 2950–2957. doi: 10.1021/ci300447c
Silicos-IT. https://www.silicos-it.be/ (accessed on: September 24, 2023)
Wang X., Bove A. M., Simone G., Ma B. Molecular bases of VEGFR-2-mediated physiological function and pathological role. Front. Cell Dev. Biol. 2020; 8, art. no. 599281 (12 pp.). doi: 10.3389/fcell.2020.599281
Peng F.-W., Liu D.-K., Zhang Q.-W., Xu Y.-G., Shi L. VE-GFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012–2016). Expert Opin. Ther. Pat. 2017; 27, 987–1004. doi: 10.1080/13543776.2017.1344215
Lipinski Ch. A. Leadand drug-like compounds: the rule-of-five revolution. Drug Discov. Today Technol. 2004; 1, 337–341. doi: 10.1016/j.ddtec.2004.11.007
Veber D. F., Johnson S. R., Cheng H.-Y., Smith B. R., Ward K. W., Kopple K. D. Molecular properties that influence the oralbioavailability of drug candidates. J. Med. Chem. 2002; 45, 2615–2623. doi: 10.1021/jm020017n
Gu Y., Wang J., Li K., Zhang L., Ren H., Guo L., Sai Y., Zhang W., Su W. Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics. Cancer Chemother.Pharmacol. 2014; 74, 95–115. doi: 10.1007/s00280-014-2471-3
Kelder J., Grootenhuis P. D. J., Bayada D. M., Delbressine L. P. C., Ploemen J.-P. Polar molecular surface as a dominatingdeterminant for oral absorption and brain penetration of drugs. Pharm. Res. 1999; 16, 1514–1519. doi: 10.1023/A:1015040217741
van de Waterbeemd H., Camenish G., Folkers G., Chretien J. R., Raevsky O. A. Estimation of blood–brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Target. 1998; 6, 151–156. doi: 10.3109/10611869808997889
Levin V. A. Relationship of octanol / water partition coefficient and molecular weight to rat brain capillary permeability. J. Med. Chem.1980; 23, 682–684. doi: 10.1021/ jm00180a022
Hansch C., Leo A. J. Substituent constant for correlation analysis in chemistry and biology. New York: Wiley 1979. doi:10.1002/jps.2600690938
Ghose A. K., Herbertz T., Hudkins R. L., Dorsey B. D., Mallamo J. P. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem. Neurosci. 2012; 3, 50–68. doi: 10.1021/cn200100h
Pajouhesh H., Lenz G. R. Medicinal chemical properties of successful central nervous system drugs. NeuroRx. 2005; 2, 541–553. doi: 10.1602/neurorx.2.4.541
de Klerk D. J., Honeywell R. J., Jansen G., Peters G. J. Transporter and lysosomal mediated (multi)drug resistance to tyrosine kinase inhibitors and potential strategies to overcome resistance. Cancers (Basel) 2018; 10, art. no. 503 (27 pp.). doi: 10.3390/cancers10120503
Fischer H., Gottschlich R., Seelig A. Blood–brain barrier permeation: Molecular parameters governing passive diffusion. J. Membr. Biol. 1998; 165, 201–211. doi: 10.1007/ s002329900434
Raub T. J., Lutzke B. S., Andrus P. K., Sawada G. A., Staton B. A. Early preclinical evaluation of brain exposure in support of hitidentification and lead optimization. In: Borchardt R. T., Kerns E. H., Hageman M. J., Thakker D. R., Stevens J. L. (eds.) Optimizing the"Drug-Like" Properties of Leads in Drug Discovery. Biotechnology: Pharmaceutical Aspects, Vol. IV. New York: Springer 2006; 355–410. doi: 10.1007/978-0-387-44961-6_16
Wang R., Cong D., Bai Y., Zhang W. Case report: long-term sustained remission in a case of metastatic colon cancer with high microsatellite instability and KRAS exon 2 p.G12D mutation treated with fruquintinib after local radiotherapy: a case report and literature review. Front. Pharmacol. 2023; 14, art. no. 1207369 (8 pp.). doi: 10.3389/fphar.2023.1207369
Hoy S. M. Sintilimab: First global approval. Drugs 2019; 79, 341–346. doi: 10.1007/s40265-019-1066-z
Guo Y., Zhang W., Ying J., Zhang Y., Pan Y., Qiu W., Fan Q., Xu Q., Ma Y., Wang G., Guo J., Su W., Fan S., Tan P., Wang Y., Luo Y., Zhou H., Li J. Phase 1b/2 trial of fruquintinib plus sintilimab in treating advanced solid tumours: The dose-escalation and metastatic colorectal cancer cohort in the dose-expansion phases. Eur. J. Cancer 2023; 181, 26–37. doi: 10.1016/j.ejca.2022.12.004
Ma Sh., Chen R., Duan L., Li Ch., Yang T., Wang J., Zhao D. Efficacy and safety of toripalimab with fruquintinib in the third-line treatment of refractory advanced metastatic colorectal cancer: results of a single-arm, single-center, prospective, phase II clinical study. J. Gastrointest. Oncol. 2023; 14, 1052–1063. doi: 10.21037/jgo-23-108
Keam S. J. Toripalimab: First global approval. Drugs 2019; 79, 573–578. doi: 10.1007/s40265-019-01076-2
Ding X., Liu Y., Zhang Y., Liang J., Li Q., Hu H., Zhou Y. Efficacy and safety of fruquintinib as thirdor further-line therapy for patients with advanced bone and soft tissue sarcoma: a multicenter retrospective study. Anticancer Drugs 2023; 34, 877–882. doi: 10.1097/ CAD.0000000000001482
Zhang P., Yang Y., Gou H., Li Q. Phase II study of fruquintinib as secondor further-line therapy for patients with advanced biliary tract cancer. J. Clin. Oncol. 2023; 41(Suppl), art. no. e16161 (1 pp.). doi: 10.1200/ JCO.2023.41.16_suppl.e16161
Deng Y.-Y., Chen Y.-W., Wang M.-X., Zhu P.-F., Pan Sh.-Y., Jiang D.-Y., Chen Zh.-L., Yang L. Acute aortic dissection caused by fruquintinib for metastatic colorectal cancer–a case report and literature review. Transl. Cancer Res. 2023; 12, 177–185. doi: 10.21037/tcr-22-1872
Zhang N., Xin X., Feng N., Wu D., Zhang J., Yu T., Jiang Q., Gao M., Yang H., Zhao S., Tian Q., Zhang Zh. Combiningfruquintinib and doxorubicin in size-converted nano-drug carriers for tumor therapy. ACS Biomater. Sci. Eng. 2022; 8, 1907–1920. doi:10.1021/acsbiomaterials.1c01606

Labels

Pharmacy Clinical pharmacology

Ethical aspects of conducting clinical trials of human medicinal products

Potential impact on mental health in patients with treatment-resistant schizophrenia – clozapine augmentation with long-acting parenteral antipsychotics: a case series

Prospects of сomplex pharmaceutical composition application for pharmacological correction of metabolic syndrome

Increasing the efficiency of hypolipidemic therapy with the combined use of quercetin in patients with non-alcoholic fatty liver disease on the background of the metabolic syndrome

Analysis of medication administration in relation to food and beverages in inpatients

On the history and development of some changes in pharmacy practice – work safety in pharmacies

Beauty in books: pharmaceutical bookplates in the territory of the present Czech Republic

Úvodník

Article was published in

Czech and Slovak Pharmacy

2023 Issue 6