RESUMO
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.
Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Antineoplásicos , Inibidores Enzimáticos/farmacologia , Hidroximetil e Formil Transferases/antagonistas & inibidores , Neoplasias Pulmonares , Complexos Multienzimáticos/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Nucleotídeo Desaminases/antagonistas & inibidores , Ribonucleotídeos , Aminoimidazol Carboxamida/farmacocinética , Aminoimidazol Carboxamida/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Hidroximetil e Formil Transferases/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Complexos Multienzimáticos/metabolismo , Proteínas de Neoplasias/metabolismo , Nucleotídeo Desaminases/metabolismo , Ribonucleotídeos/farmacocinética , Ribonucleotídeos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A hallmark of cancer is unbridled proliferation that can result in increased demand for de novo synthesis of purine and pyrimidine bases required for DNA and RNA biosynthesis. These synthetic pathways are frequently upregulated in cancer and involve various folate-dependent enzymes. Antifolates have a proven record as clinically used oncolytic agents. Our recent research efforts have produced LSN 3213128 (compound 28a), a novel, selective, nonclassical, orally bioavailable antifolate with potent and specific inhibitory activity for aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT), an enzyme in the purine biosynthetic pathway. Inhibition of AICARFT with compound 28a results in dramatic elevation of 5-aminoimidazole 4-carboxamide ribonucleotide (ZMP) and growth inhibition in NCI-H460 and MDA-MB-231met2 cancer cell lines. Treatment with this inhibitor in a murine based xenograft model of triple negative breast cancer (TNBC) resulted in tumor growth inhibition.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/uso terapêutico , Fosforribosilaminoimidazolcarboxamida Formiltransferase/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Feminino , Antagonistas do Ácido Fólico/farmacocinética , Antagonistas do Ácido Fólico/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Fosforribosilaminoimidazolcarboxamida Formiltransferase/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
A series of growth hormone secretagogues (GHSs) based on 2,3-dihydroisothiazole has been synthesized in the search for a potential treatment of growth hormone deficiency or frailty in the elderly. This paper describes the evaluation of the SAR of the benzyl-D-Ser-aminoisobutyric acid dipeptide fragment. Introduction of substituents in the peptide backbone and in the phenyl ring has been investigated, as well as replacements for the benzyl group and for the AIB residue. A number of modifications resulted in enhanced potency over the parent benzyl-D-Ser-AIB derivative.
