Results sorafenib inhibits soluble epoxide hydrolase, but this inhibitory activity does not affect specific kinases. What are the possible side effects of sorafenib nexavar. Identify structure activityrelationships sarsidentify the pharmacophoreoptimize structure to improve interactions with targetdetermine toxicity and efficacy in animal modelspatent the drug continue to study drug metabolism continue to test for toxicity design a manufacturing process carry out clinical trials market the drug. Based on the structural similarity between sorafenib and soluble epoxide hydrolase inhibitors fig. Dual flt3topk inhibitor with activity against flt3itd. Nexavar sorafenib chemotherapy, side effects navigating care. Structure activity relationship studies indicated that regulation of the electron density on the pyridinepyrimidine ring to a proper degree was a key factor in improving the antitumor activity. Targets raf1 braf vegfr2 ic50 6 nm 22 nm 90 nm 1 in vitro sorafenib tosylate inhibits both wildtype and v599e mutant braf activity. The federal drug administration of us has approved sorafenib bay. The toxicity estimation software tool test was developed to allow users to easily estimate the toxicity of chemicals using quantitative structure activity relationships qsars methodologies. Sorafenib has soluble epoxide hydrolase inhibitory activity. A multikinase inhibitor for advanced renal cell carcinoma and unresectable hepatocellular carcinoma modern drug synthesis wiley online library.
Sorafenib is an oral multikinase inhibitor that is used in the therapy of advanced renal cell, liver and thyroid cancer. The study found that median survival and timetodiseaseprogression were nearly 3 months longer for patients treated with sorafenib nexavar than for patients who took placebo. We observed that a major difference in the structural scaffolds between sorafenib and seh inhibitors was the central phenylurea found in sorafenib. Sorafenib side effects, dosage, interactions drugs. Nihlb grant hl059699 and the counteract program, national institutes of health. We observed that a major difference in the structural scaffolds between sorafenib and seh inhibitors was the central phenylurea found in sorafenib and the central cyclohexylurea. Counteract program, national institutes of health office of the. Design, synthesis and biological activities of sorafenib derivatives as. It is a chemotherapy drug that works by slowing or stopping the growth of cancer cells. Qt prolongation can cause irregular heartbeats that can be life threatening. Toxicity estimation software tool test safer chemicals. Synthesis and biological evaluation of sorafeniband regorafenib. Pdf two series of novel sorafenib analogs containing a sulfonylurea.
The results suggested that the sulfonylurea sorafenib analogs are worthy of further study. A sorafenib derivative and novel shp1 agonist, sc59. In an attempt to improve the efficiency of sorafenib related treatment, we designed a series of sorafenib derivatives and conducted structure activity relationship sar studies to define a potent candidate, sc59 fig. Sorafenib accounted for approximately 7085% of the circulating analytes in plasma at steadystate. Compound 17f showed equal activity to sorafenib against mcf7 cell line, with the ic50 values of 6. Feb, 2018 structure activity relationship studies indicated that the ring c in hsd1169 was important for both flt3 kinase inhibition and proliferation inhibition. Quantitative structure activity relationship qsar model for abuseliability evaluation of designer drugs. Apr 21, 2020 sorafenib may also be used for purposes not listed in this medication guide. Thus, we further explored their kinase inhibitory activities against a large panel of protein kinases. Sorafenib has been associated with a low rate of transient elevations in serum aminotransferase levels during therapy that are generally mild and asymptomatic. Sorafenib, is a drug approved for the treatment of primary kidney cancer advanced renal cell carcinoma and advanced primary liver cancer hepatocellular carcinoma 15. Sorafenib tosylate inhibits both wildtype and v599e mutant braf activity with ic50 of 22 nm and 38 nm, respectively. Sorafenib tosylate is practically insoluble in aqueous media, slightly soluble in ethanol and soluble in peg 400.
Mar 11, 2020 heart problems like a type of abnormal heartbeat prolonged qt interval have happened with sorafenib. Qsar for beginners free software for drug designing and. Structure activity relationships sar explore the relationship between a molecules biological activity and the three dimensional structure of the molecule. Sorafenib tosylate also potently inhibits mvegfr2 flk1, mvegfr3, mpdgfr. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. However, the precise structure activity relationship and refined pharmacophore model remain to be elucidated when more abcg2 dynamic inhibitors will be available in the near future. No relationship was observed between renal function and steadystate sorafenib auc at doses of 400 mg twice daily. Cytotoxic activity against hela and hepg2 cells was demonstrated by hydrazone 17, ic 50 was 7. Design, synthesis, activity and docking study of sorafenib.
Quantitative structure activity relationships qsar and molecular docking are two of. Call your doctor right away if you have chest pain or pressure, a fast or abnormal heartbeat, shortness of breath, a big weight gain, swelling in the arms or legs, or very bad dizziness or passing out. Smallmolecule kinase inhibitors such as sorafenib and rego rafenib. Wilhelm and colleagues provide the history of this drug, which inhibits. Our previous structure activity relationship identified that taucmb and tmtucb do not inhibit the primary targets of sorafenib, craf kinase and vegfr2 kinase. Sorafenib is a protein kinase inhibitor with activity against many protein kinases, including vegfr, pdgfr and raf kinases. In examining the structure of sorafenib, it was hypothesized that this. Human abcg2, a member of the atpbinding cassette transporter superfamily, represents a promising target for sensitizing mdr in cancer chemotherapy. If the target structure is known, computational chemistry and molecular modelling software packages can be useful in identifying binding site interactions. Thus we chose sorafenib as the lead compound in order to obtain novel tyrosine kinase inhibitors with higher activity and lower side effect. Sorafenib inhibits tumour growth by blocking the activity of serinethreonine and receptor tyros ine kinases located in both the tumour cell craf, braf, v600e braf, kit, and flt3 and in the tumour vasculature craf, vegfr2.
Biological evaluation of a novel sorafenib analogue, tcupm. Dual vegf inhibition with sorafenib and bevacizumab as. Sorafenib is taken without food, 1 hour before or 2 hours after a meal. Get emergency medical help if you have signs of an allergic reaction hives, difficult breathing, swelling in your face or throat or a severe skin reaction fever, sore throat, burning eyes, skin pain, red or. Sorafenib has demonstrated proofofefficacy in the treatment of advanced renal cell carcinoma, unresectable hepatocellular carcinoma, and thyroid cancer. Docking and qsar based screening of some naturally occurring diterpenes as inhibitors of angiotensin converting enzyme ace against cardiovascular diseases. Structureactivity relationships sars and docking studies indicated that. Structure activity relationship studies of pyrazolo 3, 4d pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits flt3 and. Background pharmacology structure activity relationship sar pharmacokinetics and drug metabolism efficacy and safety syntheses sorafenib nexavar. Eight metabolites of sorafenib have been identified, of which 5 have been detected in plasma. In summary, we show, for the first time, that nontoxic dose of sorafenib. Based on the analysis of structure activity relationship of sorafenib and its analogs, we decided to keep the urea group and transform the amide group and pyridine ring into quinazoline ring. A combinatorial in silico and cellular approach to identify a.
To test this hypothesis, we first measured the inhibition potency ic 50 of sorafenib. Highlights of prescribing information these highlights do. Sorafenib is used to treat kidney, liver, and thyroid cancer. Compound 1, which lacks ring c is a poor inhibitor of flt3 and did not inhibit the growth of mv411 see table 1.
Tell your healthcare provider right away if you feel faint, lightheaded, dizzy or feel your heart beating irregularly or fast during your. Sorafenib inhibits the activity of targets present. But diaryl urea have been most extensively investigated because of sorafenib. Sorafenib has soluble epoxide hydrolase inhibitory activity, which. Sorafenib has soluble epoxide hydrolase inhibitory. Structure activity relationship studies indicated that. Sorafenib is used to treat liver cancer, thyroid cancer, or a type of kidney cancer called.
Apr 21, 2020 sorafenib tosylate is a white to yellowish or brownish solid with a molecular formula of c 21 h 16 clf 3 n 4 o 3 x c 7 h 8 o 3 s and a molecular weight of 637. Sorafenib is an oral multikinase inhibitor with activity against raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 vegfr2, plateletderived growth factor receptor pdgfr, flt3, ret, and ckit. In four phase 1 clinical trials, sorafenib was evaluated in patients with normal renal function n71 and in patients with mild renal impairment crcl 5080 mlmin, n24 or moderate renal impairment crcl 3050 mlmin, n4. Nexavar 200mg filmcoated tablets summary of product. In the current work, we present the biological data on our lead sorafenib. Based on the analysis of structure activity relationship of sorafenib.
Structure activity relationship sar analysis software programs, such as oncologic and multicase mcase, work by analyzing the chemical structure of a compound of unknown toxicity and predicting its likelihood to be a carcinogen based on comparisons to the structures of compounds with known toxicity and programmed chemical and. Sorafenib tosylate weakly inhibits fgfr1 with ic50 of 580 nm. As previously observed in the original sar study with sorafenib, conversion of a. Sorafenib tosylate bay 439006, nexavar is a multitarget inhibitor of raf1, braf and vegfr2 with ic50 of 6 nm, 22 nm and 90 nm, respectively. Biological evaluation of a novel sorafenib analogue, t.
B lethal ec 50 for each analog determined in ht1080 cells in a 10point, twofold dilution assay. Structure activity relationship sar is an approach to find qualitative relationships between chemical structure and their biological activity quantitative structure activity relationship qsar models are theoretical models that relate a. All compounds exhibited potent antiproliferative activity against hct116 and pc3 cells with. Sorafenib inhibits tumour growth of a broad spectrum of human tumour xenografts in athymic mice accompanied by a reduction of tumour angiogenesis. An economic evaluation found that the cost is extremely high relative to the degree of benefit provided by the treatment and that sorafenib nexavar is not costeffective. Thus, there seems to be different structureactivity relationships.
Jul 01, 2010 su11248 inhibits ampk activity in cultured cells. The newly potent synthetic analog of benzimidazole and the structure activity relationship. Based on the results of the rcts, sorafenib has been established as a standard agent for systemic chemotherapy in hcc patients with metastatic disease or transcatheter arterial chemoembolization tacerefractory disease. Apr 15, 2016 study of the structure activity relationships sar and common pharmacophoric features shared by various vegfr2 inhibitors, as well as analysis of binding modes of sorafenib ii pdb code 4asd. Sorafenib is an oral multikinase inhibitor that mainly targets raf kinases and receptor tyrosine kinases associated with angiogenesis vegfr23, pdgfrbeta. First, to investigate whether sc59 plus radiotherapy act. Identify structure activity relationships sarsidentify the pharmacophoreoptimize structure to improve interactions with targetdetermine toxicity and efficacy in animal modelspatent the drug.
Compounds 2, 3, 4 hsd1169 and 5 contain 4, 5, 6 and 7membered ring. The 3cf 34cl phenyl moiety in the chemical structure of sorafenib was also modified and evaluated to identify an optimal substitution pattern. Pdf pharmacological inhibition of cystineglutamate. Nov 09, 2018 sorafenib is a cancer medication that interferes with the growth and spread of cancer cells in the body. In the current study, a novel 6,7dihydro5hcyclopentadpyrimidine scaffold was designed using different molecular modelling protocols. Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Su11248 sunitinib directly inhibits the activity of. Comparative effect of tyrosine kinase inhibitors in human. Normal university and program of key laboratory of drug design and. Synthesis and biological evaluation of sorafenib bruce hammock. Nexavar sorafenib side effects, images, uses, dosage. Qsars are mathematical models used to predict measures of toxicity from the physical characteristics of the structure of chemicals known as molecular. No relationship was observed between renal function and steadystate sorafenib. A quantitative structureactivity relationship qsar study of some.
Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptordependent cancers. Sorafenib treatment induces autophagy, which may suppress tumor growth. Herein, we reported the application of our highly active catalyst 2 in the synthesis of novel sorafenib analogs containing a 1,2,3triazole moiety. The newly potent synthetic analog of benzimidazole and the structure activity relationship is shown in fig. A combinatorial in silico and cellular approach to.
Although all of the target compounds showed less activity than the positive compounds, structure activity relationships sars and docking studies indicated that sulfonylurea unit is important to the activity of this kind of compounds. Synthesis and biological evaluation of sorafenib and. Although lots of abcg2 inhibitors were identified, none of them has been tested clinically, maybe because of several problems such as toxicity or safety and pharmacokinetic uncertainty of compounds with novel chemical structures. Jan 25, 2020 sorafenib may increase the serum concentration of warfarin. Structureactivity relationship sar study and design. Structure activity relationship sar analysis of erastin. Synthesis and antitumor activity of triazolecontaining. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase phgdh, the first enzyme of the pathway, to sustain cancer. Your healthcare provider may do tests during your treatment with nexavar to check the levels of potassium, magnesium, and calcium in your blood, and check the electrical activity. Sorafenib bay 439006 is a potent inhibitor of raf1 with ic50 values of 6 nm, 22 nm and 90 nm for raf1, braf, and vegfr2 respectively, bay 439006 suppresses both wildtype and v599e mutant braf activity in vitro. Mechanism of sorafenib resistance in patients with. As a kinaseindependent sorafenib derivative, sc59 did not inhibit raf1 activity fig. In december 2005, sorafenib became the first new treatment to be approved for advanced renal cancer in more than a decade.
Your healthcare provider may do tests during your treatment with nexavar to check the levels of potassium, magnesium, and calcium in your blood, and check the electrical activity of your heart. A structures of sorafenib and common seh inhibitors. Sorafenib caused embryofetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Based on its mechanism of action and findings in animals, nexavar may cause fetal harm when administered to a pregnant woman.
Sorafenib is unique in targeting the raf mek erk pathway map kinase pathway. Sorafenib has also been linked to rare instances of clinically. Based on this hypothesis, we designed a structure activity relationship sar study to investigate the structural overlap between sorafenib and seh inhibitors. Structureactivity relationships sars and docking studies indicated that the. Structureactivity relationship of indoletethered pyrimidine.
1380 1588 888 841 335 936 1560 864 684 21 119 1211 1410 962 242 472 1427 1605 1361 1526 1447 533 1316 448 1283 785 432 732 910 923 68 190 1197 1470 1412 267 27 954 1207