Pralatrexate

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Pralatrexate
Pralatrexate.png
Systematic (IUPAC) name
N-(4-{1-[(2,4-diaminopteridin-6-yl)methyl]but-3-yn-1-yl}benzoyl)-L-glutamic acid
Clinical data
Trade names Folotyn
AHFS/Drugs.com monograph
Licence data US FDA:link
Pregnancy cat.
  • D
Legal status
Routes Intravenous
Identifiers
CAS number 146464-95-1 N
ATC code L01BA05
PubChem CID 148121
ChemSpider 130578 YesY
UNII A8Q8I19Q20 YesY
ChEBI CHEBI:71223 N
ChEMBL CHEMBL1201746 N
Chemical data
Formula C23H23N7O5 
Mol. mass 477.47 g/mol
 N (what is this?)  (verify)

Pralatrexate (brand name Folotyn) is an anti-cancer therapy.[1] It is the first drug approved as a treatment for patients with relapsed or refractory peripheral T-cell lymphoma, or PTCL[2] — a biologically diverse group of aggressive blood cancers that have a poor prognosis.[2]

Approval[edit]

Folotyn was approved by the U.S. Food and Drug Administration (FDA) in September 2009 under the FDA’s accelerated approval,[2] which allows for earlier approval of drugs that meet unmet medical needs.[3] Pralatrexate injection is marketed in the U.S. under the name Folotyn by Spectrum Pharmaceuticals.[2] Clinical trials are currently underway to explore the potential of Folotyn in other blood related cancers and solid tumors.[4]

Mechanism[edit]

Pralatrexate is an antifolate (a folate analogue metabolic inhibitor) designed to accumulate preferentially in cancer cells.[1] Based on preclinical studies, researchers believe that pralatrexate selectively enters cells expressing reduced folate carrier type 1 (RFC-1), a protein that is overexpressed on certain cancer cells compared to normal cells.[1]

Antifolates, such as pralatrexate, are part of a group of compounds known as antimetabolites with structural similarity to naturally occurring molecules involved in DNA synthesis.[5] Cancer cells mistake antimetabolites for normal metabolites[5] allowing the compound to stop or slow critical enzymes involved in DNA synthesis which then triggers cell death.[1] Because of their primary effect on DNA synthesis, the antimetabolites are most effective against actively dividing cells and are largely cell-cycle phase specific.[5]

Discovery[edit]

Research on this class of drugs began in the 1950s at SRI International, where scientists were focused on developing new chemotherapies and antifolates that would be effective against tumor cells.[1]

In the late 1970s, researchers at Memorial Sloan Kettering Cancer Center discovered that cancerous cells take in natural folate through a protein identified as plasma membrane transporter (now referred to as “reduced folate carrier type 1” or “RFC-1”). Further research showed that when normal cells evolve into cancerous cells they often overproduce RFC-1 to ensure they get enough folate.[6]

A subsequent scientific collaboration was ultimately formed among SRI International, Memorial Sloan Kettering Cancer Center, and the Southern Research Institute with the intention of developing an antifolate with greater therapeutic selectivity – an agent that could be more effectively internalized into tumors (transported into the cells through RFC-1) and would be more toxic to cancer cells than normal cells.[6]

This collaboration, supported by the National Cancer Institute,[7] led to the identification of pralatrexate in the mid-1990s. Pralatrexate was later licensed to Allos Therapeutics in 2002 for further development.[8] Allos Therapeutics, Inc. was acquired by Spectrum Pharmaceuticals, Inc. on September 5, 2012. Allos is now a wholly owned subsidiary of Spectrum.[9]

References[edit]

  1. ^ a b c d e [1], Allos Therapeutics Press Release, “Allos Therapeutics' Pralatrexate Demonstrates Anticancer Activity in Multiple Cancer Cell Lines”.
  2. ^ a b c d [2], Allos Therapeutics Press Release, “Allos Therapeutics' FOLOTYN(TM) First and Only FDA-Approved Therapy for Relapsed or Refractory Peripheral T-cell Lymphoma”.
  3. ^ [3], FDA, “Fast Track, Accelerated Approval and Priority Review”.
  4. ^ [4], Allos Therapeutics, “Allos Therapeutics, Inc. Q1 2010 Earnings Call Transcript”.
  5. ^ a b c [5], Psychiatric Times, “Principles of Oncologic Pharmacotherapy”.
  6. ^ a b [6], Memorial Sloan Kettering Cancer Center Press Release, “FDA Approves Lymphoma Drug Developed at Memorial Sloan Kettering”.
  7. ^ [7], National Cancer Institute “NCI Cancer Bulletin: The Next Steps in Drug Development at NCI”.
  8. ^ "FDA Approves Pralatrexate for Treatment of Peripheral T-Cell Lymphoma" (Press release). SRI International. 2009-09-25. Retrieved 2013-07-10. 
  9. ^ Avery, Greg (2012-09-07). "Purchase of Allos Therapeutics is completed". Denver Business Journal. Retrieved 2013-07-10. 

External links[edit]