Year-end Sale % OFF 
Abstract
AICARFT is a folate dependent catalytic site within the ATIC gene, part of the purine biosynthetic pathway, a pathway frequently upregulated in cancers. LSN3213128 is a potent (16 nM) anti-folate inhibitor of AICARFT and selective relative to TS, SHMT1, MTHFD1, MTHFD2 and MTHFD2L. Increases in ZMP, accompanied by activation of AMPK and cell growth inhibition, were observed with treatment of LY3213128. These effects on ZMP and proliferation were dependent on folate levels. In human breast MDA-MB-231met2 and lung NCI-H460 cell lines, growth inhibition was rescued by hypoxanthine, but not in the A9 murine cell line which is deficient in purine salvage. In athymic nude mice, LSN3213128 robustly elevates ZMP in MDA-MB-231met2, NCI-H460 and A9 tumors in a time and dose dependent manner. Significant tumor growth inhibition in human breast MDA-MB231met2 and lung NCI-H460 xenografts and in the syngeneic A9 tumor model were observed with oral administration of LSN3213128. Strikingly, AMPK appeared activated within the tumors and did not change even at high levels of intratumoral ZMP after weeks of dosing. These results support the evaluation of LSN3213128 as an antineoplastic agent.
Highlights
Pemetrexed is a classical anti-folate that inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) and 5-aminoimidazole 4-carboxamide ribonucleotide transformylase inosine monophosphate cyclohydrolase (ATIC)[1]
In order to test the hypothesis that the inhibition of purine biosynthesis with concomitant AMP-dependent protein kinase (AMPK) activation via ZMP will lead to anti-tumor efficacy, we developed a non-classical anti-folate, LSN3213128, as a novel and selective inhibitor of AICARFT15
LSN3213128 (Fig. 1B) is a potent folate inhibitor of AICARFT which binds in the folate binding pocket with ZMP (Fig. 1C) resulting in an IC50 of 16 ± 11 nM for the conversion of ZMP to IMP
Summary
Pemetrexed is a classical anti-folate that inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT) and 5-aminoimidazole 4-carboxamide ribonucleotide transformylase inosine monophosphate cyclohydrolase (ATIC)[1]. Further investigation of pemetrexed showed that the inhibition of ATIC by pemetrexed leads to elevation of 5-aminoimidazole 4-carboxamide ribonucleotide (ZMP) and the activation of AMP-activated Protein Kinase (AMPK), suggesting that effects of pemetrexed on the ZMP/AMPK pathway may contribute to its anti-tumor activity(Fig. 1A)[3]. The ZMP intermediate in purine biosynthesis and its metabolite, 5-aminoimidazole 4-carboxamide ribonucleoside (AICAR), is remarkable because ZMP is an energy sensor[5]. Activated AMPK phosphorylates PCG-1α, HDAC, TSC1/2, Raptor and ACC111. In order to test the hypothesis that the inhibition of purine biosynthesis with concomitant AMPK activation via ZMP will lead to anti-tumor efficacy, we developed a non-classical anti-folate, LSN3213128, as a novel and selective inhibitor of AICARFT15. LSN3213128 is used to explore the consequence of ZMP elevation in solid tumors
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
