Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction

Mayr, Fabian; Moeller, Gabriele; Garscha, Ulrike; Fischer, Jana; Castaño, Patricia Rodríguez; Inderbinen, Silvia G.; Temml, Veronika; Waltenberger, Birgit; Schwaiger, Stefan; Hartmann, Rolf W.; Gege, Christian; Martens, Stefan; Odermatt, Alex; Pandey, Amit V.; Werz, Oliver; Adamski, Jerzy; Stuppner, Hermann; Schuster, Daniela

doi:10.1101/2020.07.01.181859

Cited by 4 publications

(2 citation statements)

References 82 publications

(65 reference statements)

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“…In a previous study, Mayr et al described the general suitability of various natural chalcones as potential AKR1C3 inhibitors [ 39 ]. In this work, 11 closely related natural products with a dihydrochalcone or chalcone skeleton were submitted to enzyme inhibition assays on 17β-hydroxysteroid dehydrogenases 3 and 4, but most importantly AKR1C3.…”

Section: Resultsmentioning

confidence: 99%

Dual Inhibitory Action of a Novel AKR1C3 Inhibitor on Both Full-Length AR and the Variant AR-V7 in Enzalutamide Resistant Metastatic Castration Resistant Prostate Cancer

Kafka

Mayr

Temml

et al. 2020

Cancers

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The expanded use of second-generation antiandrogens revolutionized the treatment landscape of progressed prostate cancer. However, resistances to these novel drugs are already the next obstacle to be solved. Various previous studies depicted an involvement of the enzyme AKR1C3 in the process of castration resistance as well as in the resistance to 2nd generation antiandrogens like enzalutamide. In our study, we examined the potential of natural AKR1C3 inhibitors in various prostate cancer cell lines and a three-dimensional co-culture spheroid model consisting of cancer cells and cancer-associated fibroblasts (CAFs) mimicking enzalutamide resistant prostate cancer. One of our compounds, named MF-15, expressed strong antineoplastic effects especially in cell culture models with significant enzalutamide resistance. Furthermore, MF-15 exhibited a strong effect on androgen receptor (AR) signaling, including significant inhibition of AR activity, downregulation of androgen-regulated genes, lower prostate specific antigen (PSA) production, and decreased AR and AKR1C3 expression, indicating a bi-functional effect. Even more important, we demonstrated a persisting inhibition of AR activity in the presence of AR-V7 and further showed that MF-15 non-competitively binds within the DNA binding domain of the AR. The data suggest MF-15 as useful drug to overcome enzalutamide resistance.

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Section: Resultsmentioning

confidence: 99%

Dual Inhibitory Action of a Novel AKR1C3 Inhibitor on Both Full-Length AR and the Variant AR-V7 in Enzalutamide Resistant Metastatic Castration Resistant Prostate Cancer

Kafka

Mayr

Temml

et al. 2020

Cancers

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“…We investigated synthetic and semi-synthetic derivatives of MF-15, a benzylated dihydrochalcone isolated from Melodorum fruticosum leaves, in an in silico profiling approach and discovered several distinct bioactivities on individual protein targets. One or a combination of these activities lead to in vitro anti-proliferative activity on different cancer cell lines, previously published in 1 and 2 .…”

mentioning

confidence: 97%

Natural product analogues from the dihydrochalcone series as multi-target inhibitors of cancer cell growth

Huber-Cantonati

Temml

Mähr

et al. 2022

GA – 70th Annual Meeting 2022

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Synthesis of Pyrrolo[3,4-b]pyridin-5-ones via Ugi–Zhu Reaction and In Vitro–In Silico Studies against Breast Carcinoma

Morales-Salazar,

Garduño-Albino,

Montes-Enríquez

et al. 2023

Pharmaceuticals

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An Ugi–Zhu three-component reaction (UZ-3CR) coupled in a one-pot manner to a cascade process (N-acylation/aza Diels–Alder cycloaddition/decarboxylation/dehydration) was performed to synthesize a series of pyrrolo[3,4-b]pyridin-5-ones in 20% to 92% overall yields using ytterbium triflate as a catalyst, toluene as a solvent, and microwaves as a heat source. The synthesized molecules were evaluated in vitro against breast cancer cell lines MDA-MB-231 and MCF-7, finding that compound 1f, at a concentration of 6.25 μM, exhibited a potential cytotoxic effect. Then, to understand the interactions between synthesized compounds and the main proteins related to the cancer cell lines, docking studies were performed on the serine/threonine kinase 1 (AKT1) and Orexetine type 2 receptor (Ox2R), finding moderate to strong binding energies, which matched accurately with the in vitro results. Additionally, molecular dynamics were performed between proteins related to the studied cell lines and the three best ligands.

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Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction

Cited by 4 publications

References 82 publications

Dual Inhibitory Action of a Novel AKR1C3 Inhibitor on Both Full-Length AR and the Variant AR-V7 in Enzalutamide Resistant Metastatic Castration Resistant Prostate Cancer

Dual Inhibitory Action of a Novel AKR1C3 Inhibitor on Both Full-Length AR and the Variant AR-V7 in Enzalutamide Resistant Metastatic Castration Resistant Prostate Cancer

Natural product analogues from the dihydrochalcone series as multi-target inhibitors of cancer cell growth

Synthesis of Pyrrolo[3,4-b]pyridin-5-ones via Ugi–Zhu Reaction and In Vitro–In Silico Studies against Breast Carcinoma

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