Structure‐Based Design and Characterization of Axitinib

Kania, Robert S.

doi:10.1002/9780470524961.ch7

Cited by 20 publications

(18 citation statements)

References 53 publications

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“…There is a great deal of evidence that for the interactions with ligands, Cys919 is an important amino acid present in the VEGFR2 domain [29,[32][33][34]. For example, it was reported that the Cys919 amide group made a hydrogen bond to the ligand for pazopanib, axitinib, and sunitinib as well as its methoxy analogue [15,16,30]. Our studies have shown that the hydrogen contact involving Cys919 can be observed only for indazole 7.…”

Section: Posementioning

confidence: 60%

“…Regarding the above discussion, we can conclude that indazoles 2-6 quinoline 9 interact with the amino acids present in the VEGFR2 pocket in a similar manner to the known drugs like pazopanib, axitinib, or sorafenib [15,16,36], i.e., by forming contacts with Cys 868, Glu885, Cys919, or Phe1047.…”

Section: Posementioning

confidence: 81%

“…Pazopanib and axitinib are small-molecule multikinase inhibitors, but they are especially effective in angiogenesis blockage through VEGFR signalling pathway inhibition. Both these drugs were approved for the therapy of metastatic renal cell carcinoma in 2009 and 2012, respectively, and Pazopanib got another FDA approval for soft tissue sarcoma in 2012 [ 11 , 15 , 16 ]. Another multitargeted indazole analogue—entrectinib, albeit is a weaker VEGFR2 inhibitor and acts mainly as a TRKA/B/C, ROS1, and ALK kinases blocking agent—was successfully examined as a promising agent for the treatment of haematologic malignancies [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Theoretical Investigations on Interactions of Arylsulphonyl Indazole Derivatives as Potential Ligands of VEGFR2 Kinase

Czaja

Kujawski

Śliwa

et al. 2020

IJMS

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Vascular endothelial growth factor receptor 2 (VEGFR2) is a key receptor in the angiogenesis process. The VEGFR2 expression is upregulated in many cancers so this receptor is an important target for anticancer agents. In the present paper, we analyse interactions of several dimeric indazoles, previously investigated for anticancer activity, with the amino acids present in the VEGFR2 binding pocket. Using the docking method and MD simulations as well as theoretical computations (SAPT0, PIEDA, semi-empirical PM7), we confirmed that these azoles can efficiently bind into the kinase pocket and their poses can be stabilised by the formation of hydrogen bonds, π–π stacking, π–cation, and hybrid interactions with some amino acids of the kinase cavity like Ala866, Lys868, Glu885, Thr916, Glu917, and Phe918.

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Section: Posementioning

confidence: 60%

Section: Posementioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Theoretical Investigations on Interactions of Arylsulphonyl Indazole Derivatives as Potential Ligands of VEGFR2 Kinase

Czaja

Kujawski

Śliwa

et al. 2020

IJMS

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“…Axitinib (Inlyta; Pfizer Inc, New York, New York), a potent and selective small molecule inhibitor of VEGFR‐1 to VEGFR‐3, binds to the inactive conformation of the catalytic domain of VEGF RTKs . Studies in adults have established a maximum tolerated dose (MTD) of 5 mg orally twice daily, and provided guidelines for intrapatient dose titration to a maximum of 10 mg orally twice daily .…”

Section: Introductionmentioning

confidence: 99%

“…[10][11][12] Axitinib (Inlyta; Pfizer Inc, New York, New York), a potent and selective small molecule inhibitor of VEGFR-1 to VEGFR-3, binds to the inactive conformation of the catalytic domain of VEGF RTKs. [13][14][15] Studies in adults [16][17][18][19][20][21][22][23][24] have established a maximum tolerated dose (MTD) of 5 mg orally twice daily, and provided guidelines for intrapatient dose titration to a maximum of 10 mg orally twice daily. 22 Common adverse effects include diarrhea, hypertension, fatigue, anorexia, nausea, weight loss, dysphonia, palmar-plantar erythrodysesthesia syndrome, proteinuria, and vomiting.…”

Section: Introductionmentioning

confidence: 99%

A study of axitinib, a VEGF receptor tyrosine kinase inhibitor, in children and adolescents with recurrent or refractory solid tumors: A Children’s Oncology Group phase 1 and pilot consortium trial (ADVL1315)

Geller

Fox

Turpin

et al. 2018

Cancer

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Background Axitinib is an oral small molecule that inhibits receptor tyrosine kinases VEGFR1-3. A phase I and pharmacokinetic trial evaluating axitinib was conducted in children with refractory solid tumors. Methods Axitinib was administered orally, twice daily, in continuous 28-day cycles. Dose levels (2.4 and 3.2 mg/m2/dose) were evaluated using a rolling 6 design. Serial pharmacokinetics (PK) (cycle 1 days 1 and 8), and exploratory biomarkers were analyzed. Results Nineteen patients were enrolled; one patient was ineligible due to inadequate time elapsed from prior therapy. The median age was 13.5 years (range 5–17 years). Two of five patients treated at dose level 2 experienced DLT (palmar-plantar erythryodysesthesia syndrome (1); intratumoral hemorrhage (1)). Frequent (>20%) grade 1–2 toxicity during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Non-hematological grade ≥ 3 toxicity in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, median time to peak plasma concentration was 2 hours (h) and half-life ranged from 0.7–5.2 h. Exposure and dose were not significantly associated with hypertension. Five patients had stable disease for ≥ 6 cycles as best response including patients with malignant peripheral nerve sheath tumor (1), Ewing sarcoma (1), hepatocellular carcinoma (1), and osteosarcoma (2). One patient with alveolar soft part sarcoma had a partial response. Kidney injury biomarkers were elevated at baseline; no trends were identified. Conclusions In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib is 2.4 mg/m2/dose, which provides pharmacokinetic exposures similar to adults.

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VEGFR/Multikinase Inhibitors

2023

Molecules Engineered Against Oncogenic Proteins and Cancer

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Structure‐Based Design and Characterization of Axitinib

Cited by 20 publications

References 53 publications

Theoretical Investigations on Interactions of Arylsulphonyl Indazole Derivatives as Potential Ligands of VEGFR2 Kinase

Theoretical Investigations on Interactions of Arylsulphonyl Indazole Derivatives as Potential Ligands of VEGFR2 Kinase

A study of axitinib, a VEGF receptor tyrosine kinase inhibitor, in children and adolescents with recurrent or refractory solid tumors: A Children’s Oncology Group phase 1 and pilot consortium trial (ADVL1315)

VEGFR/Multikinase Inhibitors

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