更新于：2024-11-01

DHFR x Folate x TYMS

更新于：2024-11-01

基本信息

关联

项与 DHFR x Folate x TYMS 相关的药物

hDHFR-NADPH-dhf249

靶点

DHFR x Folate x TYMS

作用机制

DHFR抑制剂 [+2]

在研机构

Hauptman Woodward Medical Research Institute, Inc.

原研机构

Hauptman Woodward Medical Research Institute, Inc.

在研适应症-

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 DHFR x Folate x TYMS 相关的临床结果

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100 项与 DHFR x Folate x TYMS 相关的转化医学

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0 项与 DHFR x Folate x TYMS 相关的专利（医药）

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项与 DHFR x Folate x TYMS 相关的文献（医药）

2024-08-09·ACS Infectious Diseases

Identification of Innovative Folate Inhibitors Leveraging the Amino Dihydrotriazine Motif from Cycloguanil for Their Potential as Anti-Trypanosoma brucei Agents

Article

作者: Tavares, Joana ; Tagliazucchi, Lorenzo ; Konchie Simo, Claude U ; Landi, Giacomo ; Rizzo, Marco ; Tonelli, Michele ; Schenone, Silvia ; Cordeiro-da-Silva, Anabela ; Saporito, Giulia ; Costi, Maria Paola ; Santarém, Nuno ; Carbone, Anna ; Pozzi, Cecilia ; Mangani, Stefano ; Francesconi, Valeria

Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. Based on the amino dihydrotriazine motif of the drug Cycloguanil (Cyc), a known inhibitor of both folate enzymes, we have identified two novel series of inhibitors, the 2-amino triazino benzimidazoles (1) and 2-guanidino benzimidazoles (2), as their open ring analogues. Enzymatic screening was carried out against PTR1, DHFR, and thymidylate synthase (TS). The crystal structures of TbDHFR and TbPTR1 in complex with selected compounds experienced in both cases a substrate-like binding mode and allowed the rationalization of the main chemical features supporting the inhibitor ability to target folate enzymes. Biological evaluation of both series was performed against T. brucei and L. infantum and the toxicity against THP-1 human macrophages. Notably, the 5,6-dimethyl-2-guanidinobenzimidazole 2g resulted to be the most potent (K_i = 9 nM) and highly selective TbDHFR inhibitor, 6000-fold over TbPTR1 and 394-fold over hDHFR. The 5,6-dimethyl tricyclic analogue 1g, despite showing a lower potency and selectivity profile than 2g, shared a comparable antiparasitic activity against T. brucei in the low micromolar domain. The dichloro-substituted 2-guanidino benzimidazoles 2c and 2d revealed their potent and broad-spectrum antitrypanosomatid activity affecting the growth of T. brucei and L. infantum parasites. Therefore, both chemotypes could represent promising templates that could be valorized for further drug development.

2019-06-01·Cell Chemical Biology1区 · 生物学

Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents

1区 · 生物学

Article

作者: Hajian, Behnoush ; Cynamon, Michael ; Mikušová, Katarína ; Scocchera, Eric ; G-Dayanandan, Narendran ; Viswanathan, Kishore ; Erlandsen, Heidi ; Wright, Dennis ; Korduláková, Jana ; Shoen, Carolyn ; Estrada, Alexavier ; Krucinska, Jolanta

The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity.

2019-04-01·Cancer Chemotherapy and Pharmacology4区 · 医学

Folate pathway genetic polymorphisms modulate methotrexate-induced toxicity in childhood acute lymphoblastic leukemia

4区 · 医学

Article

作者: Alsheikh, Abrar ; Alshamaseen, Daniah ; Yousef, Al-Motassem ; Zawiah, Mohammed ; Farhad, Rand ; Kadi, Taha

BACKGROUNDAcute lymphoblastic leukemia (ALL) is one of the major malignancies affecting children in Jordan. Methotrexate (MTX) is the cornerstone of chemotherapy for ALL, and works by targeting enzymes involved in the folate pathway. We hypothesize that genetic polymorphisms of the folate pathway are associated with MTX toxicity in children with ALL.METHODSA total of 64 children with ALL were included in this study; 31 (48.4%) boys and 33 (51.6%) girls aged 2-16 years. The folate pathway genes were genotyped using polymerase chain reaction followed by sequencing and studying the association between genetic polymorphisms and MTX toxicity.RESULTSThe immunophenotype was B-lineage in 55 patients (85.9%) and T-lineage in nine patients (14.1%). All genetic polymorphisms, except for dihydropyrimidine dehydrogenase polymorphisms, were associated with hematological toxicities and did not appear to precipitate any non-hematological adverse events. Patients with ALL carrying dominant alleles of methylene tetrahydrofolate (MTHFR) C677T and dihydrofolate reductase 19 bp deletion were at a higher risk of developing severe leucopenia [OR (95% CI) = 4.5 (1.2-17), p = 0.03; 5.4 (1.6-17.8); p = 0.006] while minor allele carriers of MTHFR A1298C were more likely to develop neutropenia [OR (95% CI) = 6.1 (1.3-29.5); 0.04]. Furthermore, dominant allele carriers of thymidylate synthase 1494 del6 were at a higher risk of developing neutropenia [OR (95% CI) = 6 (1.2-31.1); p = 0.04].CONCLUSIONGenetic polymorphisms of the folate pathway may modulate MTX-induced toxicity in childhood ALL.