Biology and therapeutic applications of the proton-coupled folate transporter.

Abstract

INTRODUCTION:

The proton-coupled folate transporter (PCFT; SLC46A1) was discovered in 2006 as the principal mechanism by which folates are absorbed in the intestine and the causal basis for hereditary folate malabsorption (HFM). In 2011, it was found that PCFT is highly expressed in many tumors. This stimulated interest in using PCFT for cytotoxic drug targeting, taking advantage of the substantial levels of PCFT transport and acidic pH conditions commonly associated with tumors.

AREAS COVERED:

We summarize the literature from 2006 to 2022 that explores the role of PCFT in the intestinal absorption of dietary folates and its role in HFM and as a transporter of folates and antifolates such as pemetrexed (Alimta) in relation to cancer. We provide the rationale for the discovery of a new generation of targeted pyrrolo[2,3-d]pyrimidine antifolates with selective PCFT transport and inhibitory activity toward de novo purine biosynthesis in solid tumors. We summarize the benefits of this approach to cancer therapy and exciting new developments in the structural biology of PCFT and its potential to foster refinement of active structures of PCFT-targeted anti-cancer drugs.

EXPERT OPINION:

We summarize the promising future and potential challenges of implementing PCFT-targeted therapeutics for HFM and a variety of cancers.

• Authors: Larry H Matherly, Mathew Schneider, Aleem Gangjee, Zhanjun Hou
• Journal: Expert opinion on drug metabolism & toxicology (Expert Opin Drug Metab Toxicol) Vol. 18 Issue 10 Pg. 695-706 (Oct 2022) ISSN: 1744-7607 [Electronic] England
• PMID: 36239195 (Publication Type: Journal Article)

Chemical References

• Proton-Coupled Folate Transporter
• Folic Acid Antagonists
• Pemetrexed
• Antineoplastic Agents
• Folic Acid
• SLC46A1 protein, human

Topics

• Humans
• Proton-Coupled Folate Transporter (chemistry)
• Folic Acid Antagonists (pharmacology, therapeutic use)
• Pemetrexed (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Folic Acid (therapeutic use)
• Neoplasms (drug therapy)
• Biology