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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Both antibody-based and small-molecule inhibitors have been developed as anticancer therapies, and the best-known antibody therapy is Genentech’s bevacizumab (Avastin™) which is discussed in Chapter 7. This antibody binds to the VEGF growth factor itself rather than the corresponding receptors. The first example of a small-molecule VEGFR inhibitor (semaxanib or SU-5416) was developed by Sugen (Figure 6.31). However, although it had encouraging antiangiogenic activity in in vitro and in vivo preclinical studies and was progressed to Phase III clinical trials in advanced colorectal cancer, the level of clinical activity observed did not warrant further development. Structure of semaxanib.
Tyrosine Kinase Inhibitors: Targets Other Than FLT3, BCR-ABL, and c-KIT
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Suzanne R. Hayman, Judith E. Karp
Several different compounds targeting one or more of the VEGFRs are being actively studied. One of these agents, SU5416 (Semaxinib, Pfizer Inc., New York, NY, U.S.A.), has been tested in a variety of hematological malignancies and has displayed limited clinical activity in multiple myeloma, AML, MDS, and in the myeloproliferative disorders (MPDs). Evidence of biological effects on the phosphorylation of several receptor TKs, including VEGFRs, FLT-3, and KIT, has been demonstrated. SU11248 (Sutent, Pfizer Inc., New York, NY, U.S.A.), which inhibits VEGF receptors 1, 2, PDGFR, and FLT-3, is being tested in a phase I trial in relapsed/refractory AML and is in phase III solid tumor trials treating renal cell carcinoma and gastrointestinal stromal tumors. PTK787/ZK222584 (Vatalanib, Novartis Pharmaceutical Corp., East Hanover, NJ, U.S.A.) is an orally available TK inhibitor that binds to the ATP-binding sites of VEGFR. It is now in phase II trials for MDS, and in combination with imatinib mesylate in patients with AML, AMM, and CML-BP. ZD6474 (Zactima, AstraZeneca Pharmaceuticals, Wilmington, DE, U.S.A.), a VEGFR-2 TK inhibitor, and the oral pan-VEGFR inhibitor GW786034 (GlaxoSmithKline Inc. Middlesex, UK.), which also inhibits PDGFRα and β, and c-KIT, are in phase I clinical trials in solid tumors. Other receptor TKs including AG013676 (GenBank, NIH, Maryland, U.S.) and CP-547632 (Pfizer Inc., New York, U.S.) are in the early stages of development.
Protein Function As Cell Surface And Nuclear Receptor In Human Diseases
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Urmila Jarouliya, Raj K. Keservani
Dysfunction or loss of function of the VEGF pathway has been identified in a large number of disease processes ranging from cancer to autoimmunity, retinopathy, and many more, which has led to the common perception that inhibition of the pathway would result in rapid and sustained clinical response. The development of highly specific inhibitors of both the VEGF ligand (bevacizumab, VEGF-Trap, ranibizumab) as well as the VEGF receptor (cediranib, pazopanib, sorafenib, sunitinib, vandetanib, axitinib, telatinib, semaxanib, motesanib, vatalanib, zactima) relates to the central role that this pathway plays in disease [68–74]. Blocking VEGF function has been used to treat cancer and ocular angiogenesis. VEGF could potentially be used to promote angiogenesis in clinical settings such as ischemic cardiovascular disease. VEGF gene therapy is a promising alternative treatment method for patients with severe cardiovascular diseases. VEGF inhibitor therapy either single agent or with the combination with traditional chemotherapy and/or radiation have entered the new path in human clinical trials for a wide range of diseases/therapy and/or which can be compared with the standard therapy [75]. Thus, VEGF function can be a pathologic or a beneficial agent depending upon the clinical conditions.
Metabolic activation of tyrosine kinase inhibitors: recent advance and further clinical practice
Published in Drug Metabolism Reviews, 2023
Miao Yan, Wenqun Li, Wen-Bo Li, Qi Huang, Jing Li, Hua-Lin Cai, Hui Gong, Bi-Kui Zhang, Yi-Kun Wang
Immune-related factors have also been implicated in the toxicity and adverse effects caused by drugs. Reactive TKI metabolites can lead to direct toxicity via direct adduction to neighboring host proteins or drug-metabolizing enzymes, forming reactive metabolite–protein adducts. Reactive metabolite–protein adducts can act as a hapten to stimulate the formation of neoantigens, causing the release of danger-associated molecular pattern molecules (DAMPs). DAMPs may activate antigen-presenting cells and induce immune reaction or damage. Moreover, reactive metabolites may induce an immune response through inflammasome bioactivation (Cho and Uetrecht 2017). The reactive iminoquinone metabolite of gefitinib could cause cellular damage with DAMP release from hepatocytes, which in turn could activate inflammasomes. Inflammasome activation may be essential in causing immune injury in patients exposed to gefitinib (Kato et al. 2020). The reactive sunitinib metabolites can promote DAMP release, activating inflammasomes in differentiated THP-1 cells and significantly increasing heat shock protein 90 in FLC-4 cells, which can cause immune-related injury in patients (Kato and Ijiri 2022). Activating inflammasomes by reactive metabolites also contributed to the idiosyncratic adverse events caused by semaxanib and sorafenib (Imano et al. 2021).
Effects of multi-kinase inhibitors on the activity of cytochrome P450 2J2
Published in Xenobiotica, 2022
Ayaka Kojima, Masayuki Nadai, Norie Murayama, Hiroshi Yamazaki, Miki Katoh
AA, AEE788, apatinib, astemizole, axitinib, lenvatinib, and pazopanib were purchased from Cayman Chemicals (Ann Arbour, MI, USA). Brivanib, cediranib, foretinib, linifanib, motesanib, orantinib, semaxinib, tivozanib, vandetanib, and vatalanib were obtained from AdooQ Biosciences (Irvine, CA, USA). Cabozantinib S-malate and nintedanib were purchased from LC Laboratories (Woburn, MA, USA) and MedChem Express (Monmouth Junction, NJ, USA), respectively. Danazol and midazolam were obtained from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). O-Desmethylastemizole was purchased from Toronto Research Chemicals (North York, ON, Canada). Regorafenib and sorafenib were obtained from ChemScene (Monmouth Junction, NJ, USA). Sunitinib was purchased from Selleck Chemicals (Houston, TX, USA). Recombinant human CYP2J2 microsomes were purchased from Corning (Corning, NY, USA). The 14,15-EET/DHET ELISA kit was purchased from Detroit R&D Systems (Detroit, MI, USA).
Ophthalmological Aspects of von-Hippel–Lindau Syndrome
Published in Seminars in Ophthalmology, 2021
Hashim Ali Khan, Muhammad Aamir Shahzad, Fatima Iqbal, Muhammad Amer Awan, Qaim Ali Khan, Ali Osman Saatci, Ahmed Abbass, Fazil Hussain, Syed Arif Hussain, Atif Ali, Wajahat Ali
With growing evidence about the role of VEGF in the pathogenesis of RCH in VHL, anti-VEGF drugs were assumed to regress the RCH in VHL disease.6,16,21,22,24,57 Systemic administration of SU5416 (semaxanib), an anti-VEGF agent, was able to reduce the retinal edema and exudation; however, tumor size was not changed.92–94 Similar results have been reported from case reports, small case series, and non-randomized trials using intravitreal anti-VEGF agents. Nonetheless, Wong et al.95 administered 0.5 mg intravitreal ranibizumab in patients with RCH refractory to standard treatments. After a mean of 10 injections over an average of 47 weeks, there were no improvements in tumor size or retinal exudation and one eye developed de novo tumor and enlargement of an existing tumor. However, they injected eyes with large RCH that may be refractory to the anti-VEGF drugs.95