Description

Pemetrexed is a multi-targeted antifolate with antitumor activity. It potently inhibits folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase (K_i = 109 nM), dihydrofolate reductase (K_i = 7 nM), glycinamide ribonucleotide formyltransferase (K_i = 9.3 μM), and aminoimidazole carboxamide ribonucleotide formyltransferase (K_i = 3.6 μM)¹. A clinically useful anticancer agent². Indirectly activates the metabolic kinase AMPK and consequently influences the mTORC1 pathway in human carcinomas³. Activation of AMPK is associated with pemetrexed resistance⁴. Induces G₀/G₁-phase cell cycle arrest in esophageal squamous cell carcinoma cells⁵.

References:

1. Shih, Chuan, et al. "LY231514, a pyrrolo [2, 3-d] pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes." Cancer research 57.6 (1997): 1116-1123.

2. Hanauske, Axel-R., et al. "Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors." The Oncologist 6.4 (2001): 363-373.

3. Rothbart, Scott B., Alexandra C. Racanelli, and Richard G. Moran. "Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas." Cancer research 70.24 (2010): 10299-10309.

4. Qin, Yiyang, et al. "AMPK activation induced in pemetrexed‐treated cells is associated with development of drug resistance independently of target enzyme expression." Molecular oncology 13.6 (2019): 1419-1432.

5. Li, Xinying, et al. "Pemetrexed exerts anticancer effects by inducing G0/G1‑phase cell cycle arrest and activating the NOXA/Mcl‑1 axis in human esophageal squamous cell carcinoma cells." Oncology letters 17.2 (2019): 1851-1858.