Pelitrexol

Pelitrexol
Clinical data
Other names	AG2037; AG-2037
Identifiers
	IUPAC name (2S)-2-[[5-[2-[(6S)-2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-6-yl]ethyl]-4-methylthiophene-2-carbonyl]amino]pentanedioic acid;
CAS Number	446022-33-9;
PubChem CID	135431074;
DrugBank	DB12757;
UNII	DHT6E8M4KP;
Chemical and physical data
Formula	C20H25N5O6S
Molar mass	463.51 g·mol−1

Pelitrexol (development code AG2037) is a purine biosynthesis inhibitor used in cancer treatment research, specifically targeting the enzyme glycinamide ribonucleotide formyltransferase (GARFT). It has been studied for its potential in inhibiting tumor growth by reducing purine nucleotide pools, which in turn suppresses mTORC1 activity and disrupts cancer cell proliferation.

Mechanism of action

Pelitrexol inhibits the GARFT enzyme, an essential component of de novo purine biosynthesis. This leads to a reduction in intracellular guanine nucleotides, which impairs Rheb activation, thereby inhibiting mTORC1 activity. The drug disrupts both protein synthesis and tumor growth by impacting cell cycle progression and nucleotide availability.^[1]

Antitumor activity

Pelitrexol has shown significant tumor-suppressive effects in non-small-cell lung cancer (NSCLC) models. In preclinical studies, the drug reduced mTORC1 activity, leading to robust inhibition of tumor growth in mice with NSCLC xenografts.^[1] However, development was discontinued due to limited single-agent efficacy in clinical trials.^[1]

Applications

Pelitrexol has been primarily investigated in the context of non-small-cell lung cancer and other tumors where purine biosynthesis is essential for cancer cell proliferation.^[1] While it has not advanced to widespread clinical use, the compound remains a valuable research tool in understanding cancer metabolism and nucleotide biosynthesis pathways.

Risks and limitations

The major limitation of pelitrexol is its lack of efficacy as a standalone treatment in clinical trials. Despite its ability to inhibit purine biosynthesis and mTORC1 activity, it did not demonstrate sufficient tumor regression in patients.^[1]

References

^ ^a ^b ^c ^d ^e Emmanuel, Natasha (2017). "Purine Nucleotide Availability Regulates mTORC1 Activity through the Rheb GTPase". Cell Reports. 19 (23): 2665–2680. doi:10.1016/j.celrep.2017.05.043. PMID 28658616.

[emmanuel2017-1] Emmanuel, Natasha (2017). "Purine Nucleotide Availability Regulates mTORC1 Activity through the Rheb GTPase". Cell Reports. 19 (23): 2665–2680. doi:10.1016/j.celrep.2017.05.043. PMID 28658616.

[1]