New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold

Pippione, Agnese Chiara; Kılıç-Kurt, Zühal; Kovachka, Sandra; Sainas, Stefano; Rolando, Barbara; Denasio, Enrica; Pors, Klaus; Adinolfi, Salvatore; Zonari, Daniele; Bagnati, Renzo; Lolli, Marco Lucio; Spyrakis, Francesca; Oliaro‐Bosso, Simonetta; Boschi, Donatella

doi:10.1016/j.ejmech.2022.114366

Cited by 9 publications

(8 citation statements)

References 57 publications

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“…Notably, among AKR1Cs, AKR1C3 has the largest SP1 due to a significant degree of conformational plasticity among residues involved in ligand recognition (Figure 1A). 27,42 Consistent with previous observations, a free carboxylic acid group in NSAIDs is essential for optimal inhibition of the AKR1C enzymes (Figure S1A,B). 35 It has been reported that AKR1C3 prefers to bind with R-enantiomers of arylpropionic acids.…”

Section: ■ Results and Discussionsupporting

confidence: 91%

“…The ligand binding domain of AKR1C3 consists of five characteristic compartments: highly conserved oxyanion site (OS) containing Tyr55 and His117; steroid channel (SC) for substrate recognition (Tyr24, Leu54, Ser129, and Trp227), three subpockets, including SP1 (Ser118, Asn167, Phe306, Phe311, Tyr319), SP2 (Trp86, Ser129, Trp227, Phe311), and SP3 (Tyr24, Glu192, Ser221, and Tyr305). Notably, among AKR1Cs, AKR1C3 has the largest SP1 due to a significant degree of conformational plasticity among residues involved in ligand recognition (Figure A). , …”

Section: Resultsmentioning

confidence: 99%

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Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment

Chu

et al. 2023

J. Med. Chem.

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Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumor development and chemotherapy resistance. The catalytic activity of the enzyme has been recognized as one of the important factors in inducing anthracycline (ANT) resistance in cancer cells. Inhibition of AKR1C3 activity may provide a promising approach to restore the chemosensitivity of ANT-resistant cancers. Herein, a series of biaryl-containing AKR1C3 inhibitors has been developed. The best analogue S07-1066 selectively blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected cell models. Furthermore, co-treatment of S07-1066 significantly synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7 cells overexpressing AKR1C3. The potential synergism of S07-1066 over DOX cytotoxicity was demonstrated in vitro and in vivo. Our findings indicate that inhibition of AKR1C3 potentially enhances the therapeutic efficacy of ANTs and even suggests that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.

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Section: ■ Results and Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment

Chu

et al. 2023

J. Med. Chem.

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“…% remaining compound after 1 h. This analysis was performed by TechMed III . For details see supplementary material; f Partition coefficients between n-octanol and PBS at pH 7.4 (log D 7.4 ) obtained using the shake-flask technique described in reference [41].…”

Section: Fundingmentioning

confidence: 99%

Biochemical characterization of Mycobacterium tuberculosis dihydroorotate dehydrogenase and identification of a selective inhibitor

et al. 2023

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Mycobacterium tuberculosis (MTB) is the etiologic agent of tuberculosis (TB), an ancient disease which causes 1.5 million deaths worldwide. Dihydroorotate dehydrogenase (DHODH) is a key enzyme of the MTB de novo pyrimidine biosynthesis pathway, and it is essential for MTB growth in vitro, hence representing a promising drug target. We present: (i) the biochemical characterization of the full‐length MTB DHODH, including the analysis of the kinetic parameters, and (ii) the previously unreleased crystal structure of the protein that allowed us to rationally screen our in‐house chemical library and identify the first selective inhibitor of mycobacterial DHODH. The inhibitor has fluorescence properties, potentially instrumental to in cellulo imaging studies, and exhibits an IC50 value of 43 μm, paving the way to hit‐to‐lead process.

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“…A cascade of kinases (Phospholipase C, Protein Kinase C, Mitogen Activated Protein Kinase) and transcription factors (Nuclear Factor Kappa B, Apetala-1) also result in the production of proinflammatory signals and oxidative stress, which finally cause diabetes and cancers. [11][12][13][14] Therefore, AKR1B1 is considered the most important intervention target for the treatment of diabetic complications.…”

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confidence: 99%

“…Yield: 0.47 g (72%); white powder; m.p. 165−169°C; purity: 97.11%,1 H NMR (400 MHz, [D 6 ]DMSO): δ/ppm =7.93 (dd, J = 8.5, 1.6 Hz, 1H), 7.41 (td, J = 7.8, 1.6 Hz, 1H), 7.32 (ddt, J = 8.1, 3.5, 1.1 Hz, 2H), 7.21 (td, J = 8.1, 1.3 Hz, 1H), 7.12-7.02 (m, 3H), 4.91 (s, 2H), 4.62 (t, 2H), 7.13 (dd, J = 7.2, 1.6 Hz, 1H), 7.10-7.03 (m, 2H), 5.27 (t, J = 1.0 Hz, 2H) 13. C NMR (100 MHz, chloroform-d) δ/ppm = 164.90, 163.18, 161.21, 148.25, 143.05, 133.73, 133.69, 131.05, 130.70, 130.63, 128.39, 126.42, 122.72, 118.98, 115.64, 115.45, 51.89.…”

mentioning

confidence: 99%

Design and synthesis of novel quinazolin‐4(1H)‐one derivatives as potent and selective inhibitors targeting AKR1B1

Han

et al. 2023

Archiv der Pharmazie

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Inhibition of aldose reductase (AKR1B1) is a promising option for the treatment of diabetic complications. However, most of the developed small molecule inhibitors lack selectivity or suffer from low bioactivity. To address this limitation, a novel series of quinazolin-4(1H)-one derivatives as potent and selective inhibitors of AKR1B1 were designed and synthesized. Aldose reductase inhibitory activities of the novel compounds were characterized by IC 50 values ranging from 0.015 to 31.497 μM. Markedly enhanced selectivity of these derivatives was also recorded, which was further supported by docking studies. Of these inhibitors, compound 5g exhibited the highest inhibition activity with selectivity indices reaching 1190.8. The structure-activity relationship highlighted the importance of N1-acetic acid and N3benzyl groups with electron-withdrawing substituents on the quinazolin-4(1H)-one scaffold for the construction of efficient and selective AKR1B1 inhibitors.

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New aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the hydroxytriazole scaffold

Cited by 9 publications

References 57 publications

Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment

Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment

Biochemical characterization of Mycobacterium tuberculosis dihydroorotate dehydrogenase and identification of a selective inhibitor

Design and synthesis of novel quinazolin‐4(1H)‐one derivatives as potent and selective inhibitors targeting AKR1B1

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