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Screening and in vitro testing of antifolate inhibitors of human cytosolic serine hydroxymethyltransferase.
ChemMedChem. 2015 Mar; 10(3):490-7.C

Abstract

Metabolic reprogramming of tumor cells toward serine catabolism is now recognized as a hallmark of cancer. Serine hydroxymethyltransferase (SHMT), the enzyme providing one-carbon units by converting serine and tetrahydrofolate (H4 PteGlu) to glycine and 5,10-CH2 -H4 PteGlu, therefore represents a target of interest in developing new chemotherapeutic drugs. In this study, 13 folate analogues under clinical evaluation or in therapeutic use were in silico screened against SHMT, ultimately identifying four antifolate agents worthy of closer evaluation. The interaction mode of SHMT with these four antifolate drugs (lometrexol, nolatrexed, raltitrexed, and methotrexate) was assessed. The mechanism of SHMT inhibition by the selected antifolate agents was investigated in vitro using the human cytosolic isozyme. The results of this study showed that lometrexol competitively inhibits SHMT with inhibition constant (Ki) values in the low micromolar. The binding mode of lometrexol to SHMT was further investigated by molecular docking. These results thus provide insights into the mechanism of action of antifolate drugs and constitute the basis for the rational design of novel and more potent inhibitors of SHMT.

Authors+Show Affiliations

Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le Aldo Moro 5, Roma 00185 (Italy).No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25677305

Citation

Paiardini, Alessandro, et al. "Screening and in Vitro Testing of Antifolate Inhibitors of Human Cytosolic Serine Hydroxymethyltransferase." ChemMedChem, vol. 10, no. 3, 2015, pp. 490-7.
Paiardini A, Fiascarelli A, Rinaldo S, et al. Screening and in vitro testing of antifolate inhibitors of human cytosolic serine hydroxymethyltransferase. ChemMedChem. 2015;10(3):490-7.
Paiardini, A., Fiascarelli, A., Rinaldo, S., Daidone, F., Giardina, G., Koes, D. R., Parroni, A., Montini, G., Marani, M., Paone, A., McDermott, L. A., Contestabile, R., & Cutruzzolà, F. (2015). Screening and in vitro testing of antifolate inhibitors of human cytosolic serine hydroxymethyltransferase. ChemMedChem, 10(3), 490-7. https://doi.org/10.1002/cmdc.201500028
Paiardini A, et al. Screening and in Vitro Testing of Antifolate Inhibitors of Human Cytosolic Serine Hydroxymethyltransferase. ChemMedChem. 2015;10(3):490-7. PubMed PMID: 25677305.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Screening and in vitro testing of antifolate inhibitors of human cytosolic serine hydroxymethyltransferase. AU - Paiardini,Alessandro, AU - Fiascarelli,Alessio, AU - Rinaldo,Serena, AU - Daidone,Frederick, AU - Giardina,Giorgio, AU - Koes,David R, AU - Parroni,Alessia, AU - Montini,Giulia, AU - Marani,Marina, AU - Paone,Alessio, AU - McDermott,Lee A, AU - Contestabile,Roberto, AU - Cutruzzolà,Francesca, Y1 - 2015/02/10/ PY - 2015/01/22/received PY - 2015/2/14/entrez PY - 2015/2/14/pubmed PY - 2015/12/15/medline KW - antifolates KW - cancer metabolism KW - inhibitors KW - lometrexol KW - serine hydroxymethyltransferase (SHMT) SP - 490 EP - 7 JF - ChemMedChem JO - ChemMedChem VL - 10 IS - 3 N2 - Metabolic reprogramming of tumor cells toward serine catabolism is now recognized as a hallmark of cancer. Serine hydroxymethyltransferase (SHMT), the enzyme providing one-carbon units by converting serine and tetrahydrofolate (H4 PteGlu) to glycine and 5,10-CH2 -H4 PteGlu, therefore represents a target of interest in developing new chemotherapeutic drugs. In this study, 13 folate analogues under clinical evaluation or in therapeutic use were in silico screened against SHMT, ultimately identifying four antifolate agents worthy of closer evaluation. The interaction mode of SHMT with these four antifolate drugs (lometrexol, nolatrexed, raltitrexed, and methotrexate) was assessed. The mechanism of SHMT inhibition by the selected antifolate agents was investigated in vitro using the human cytosolic isozyme. The results of this study showed that lometrexol competitively inhibits SHMT with inhibition constant (Ki) values in the low micromolar. The binding mode of lometrexol to SHMT was further investigated by molecular docking. These results thus provide insights into the mechanism of action of antifolate drugs and constitute the basis for the rational design of novel and more potent inhibitors of SHMT. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/25677305/Screening_and_in_vitro_testing_of_antifolate_inhibitors_of_human_cytosolic_serine_hydroxymethyltransferase_ L2 - https://doi.org/10.1002/cmdc.201500028 DB - PRIME DP - Unbound Medicine ER -