Vatalanib

Vatalanib (INN, codenamed PTK787 or PTK/ZK) is a small molecule protein kinase inhibitor that inhibits angiogenesis. It is being studied as a possible treatment for several types of cancer, particularly cancer that is at an advanced stage or has not responded to chemotherapy. Vatalanib is orally active, that is, it is effective when taken by mouth.

Not to be confused with Vandetanib.
Vatalanib
Clinical data
Pregnancy
category
  • None assigned
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • Investigational
Pharmacokinetic data
BioavailabilityHigh
MetabolismExtensive hepatic metabolism (mostly CYP3A4-mediated)[1]
Elimination half-life4.6 ± 1.1 h[1]
ExcretionFecal and renal[1]
Identifiers
IUPAC name
  • N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin- 1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H15ClN4
Molar mass346.82 g·mol−1
3D model (JSmol)
SMILES
  • Clc1ccc(cc1)Nc3nnc(c2c3cccc2)Cc4ccncc4
InChI
  • InChI=1S/C20H15ClN4/c21-15-5-7-16(8-6-15)23-20-18-4-2-1-3-17(18)19(24-25-20)13-14-9-11-22-12-10-14/h1-12H,13H2,(H,23,25) N
  • Key:YCOYDOIWSSHVCK-UHFFFAOYSA-N N

Vatalanib is being developed by Bayer Schering and Novartis. It inhibits all known VEGF receptors, as well as platelet-derived growth factor receptor-beta and c-kit, but is most selective for VEGFR-2.[1][2][3][4]

Development

Vatalanib was discovered through high-throughput screening.[2] It has been extensively investigated in Phase I, II and III clinical trials.[1][4] Two large, randomized controlled Phase III trials have studied the effect of adding vatalanib to the FOLFOX chemotherapy regimen in people with metastatic colorectal cancer: CONFIRM-1, whose participants had not yet received any treatment for their cancer; and CONFIRM-2, in which participants had received first-line treatment with irinotecan and fluoropyrimidines. Vatalanib produced no significant improvement in overall survival (the primary endpoint of the studies), although it did significantly increase progression-free survival in CONFIRM-2.[4] Both trials found that progression-free survival was improved in people with high levels of lactate dehydrogenase, an enzyme used as a marker of tissue breakdown; the reasons for and implications of this difference are still unclear.[4][5]

Adverse effects

The adverse effects of vatalanib appear similar to those of other VEGF inhibitors. In the CONFIRM trials, the most common side effects were high blood pressure, gastrointestinal upset (diarrhea, nausea, and vomiting), fatigue, and dizziness.[4]

Notable Users

Patrick Swayze, a popular actor in the 1980s who starred in such films as Dirty Dancing and Road House was given this drug when he was diagnosed with Stage IV Pancreatic Cancer in 2008. Doctors hoped the drug would cut off blood supply to the tumor.[6] Despite this, Swayze died on September 14, 2009, 20 months after being diagnosed.

References
  1. Jost LM, Gschwind HP, Jalava T, et al. (November 2006). "Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients". Drug Metabolism and Disposition. 34 (11): 1817–28. doi:10.1124/dmd.106.009944. PMID 16882767. S2CID 9545358.
  2. Mariani SM (2004). "Antiangiogenesis Cocktails -- Stirred or Shaken?: Highlights of the 9th Annual Drug Discovery Technology World Congress; August 8-13, 2004; Boston, Massachusetts". Medscape General Medicine. 6 (4): 21. PMC 1480579. PMID 15775848. Retrieved on October 29, 2008.
  3. Wood JM, Bold G, Buchdunger E, et al. (April 2000). "PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration". Cancer Research. 60 (8): 2178–89. PMID 10786682.
  4. Los M, Roodhart JM, Voest EE (April 2007). "Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer". The Oncologist. 12 (4): 443–50. doi:10.1634/theoncologist.12-4-443. PMID 17470687.
  5. Scott EN, Meinhardt G, Jacques C, Laurent D, Thomas AL (March 2007). "Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours". Expert Opin Investig Drugs. 16 (3): 367–79. doi:10.1517/13543784.16.3.367. PMID 17302531. S2CID 41568265.
  6. Mann, Denise. "Patrick Swayze Dies of Pancreatic Cancer". WebMD. Retrieved 3 April 2021.
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