Insights into the Inhibition of the p90 Ribosomal S6 Kinase (RSK) by the Flavonol Glycoside SL0101 from the 1.5 Å Crystal Structure of the N-Terminal Domain of RSK2 with Bound Inhibitor

Utepbergenov, Darkhan; Derewenda, Urszula; Olekhnovich, Natalya; Szukalska, Gabriela; Banerjee, Budhaditya; Hilinski, Michael K.; Lannigan, Deborah A.; Stukenberg, P. Todd; Derewenda, Zygmunt S.

doi:10.1021/bi300620c

Cited by 42 publications

(73 citation statements)

References 93 publications

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“…In a screen of botanical extracts we identified the first RSK inhibitor, SL0101 ( 1a ), which was isolated from Forsteronia refracta (20). SL0101 is an extremely specific allosteric inhibitor for the NTKD (14, 20–22). …”

Section: Introductionmentioning

confidence: 99%

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Ludwik

Campbell

et al. 2016

Molecular Cancer Therapeutics

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Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple negative breast cancer (TNBC) frequently metastasizes and high levels of activated RSK, a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate using direct pharmacological and genetic inhibition of RSK1/2 that these kinases contribute to the TNBC metastatic process in vivo. Kinase profiling demonstrated that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product, SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor, trametinib, in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo.

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Section: Introductionmentioning

confidence: 99%

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Ludwik

Campbell

et al. 2016

Molecular Cancer Therapeutics

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“…The focus for Year 2 of the project therefore turned to improving the in vitro and ex vivo potency of analogues. This goal was aided by the crystal structure of SL0101 bound to the Nterminal kinase domain of RSK2 obtained in Year 1 (6 This task was completed within the allotted timeframe. Details for each subtask follow and experimental details are attached in the appendix.…”

Section: Bodymentioning

confidence: 99%

Synthesis and Evaluation of Novel RSK Inhibitors in a Living Human Breast Model

Hilinski¹

2013

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“…Hence, they have been selected as drug target, particularly in cancer therapy (2). Several drugs targeting protein kinases have been approved by the FDA and many other small molecule inhibitors are known to be in clinical development (3,4).…”

Section: Introductionmentioning

confidence: 99%

“…Discovering novel and specific inhibitors of RSK, especially through computational methods has also been impeded by the lack of insufficient crystal structural information. It has been reported that without a proper crystal structure of RSK, the in silico studies regarding protein-inhibitor interactions had been erroneously concluded (2,6). On the other hand, the identified RSK2 inhibitors are not enough for building a reliable ligand based pharmacophore model.…”

Section: Introductionmentioning

confidence: 99%

E-Pharmacophore Mapping Combined with Virtual Screening and Molecular Docking to Identify Potent and Selective Inhibitors of P90 Ribosomal S6 Kinase (RSK)

Ece¹

2018

tjps

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TURKEYThe p90 ribosomal S6 kinases (RSK) are a family of serine/threonine protein kinases and are shown to be involved in cancer cell proliferation. The lack of highly selective inhibitors and also the lack of structural information regarding the mechanism of those inhibitors restricts the progress in this field. It has also been reported that without a proper crystal structure of RSK, the protein-inhibitor interactions in silico studies had been erroneously concluded. The first e-pharmacophore model for RSK2 has been generated in this study using recently resolved high resolution crystal structure of RSK2 in complex with LJH685 that is amongst the most potent and selective RSK inhibitors to date. 12 compounds have been suggested as promising potent and selective RSK inhibitors after the combination of virtual screening of a large database (ca. 7 million compounds with more than 144 million conformations), followed by a series of molecular docking work flow and visual inspection of all hits for critical binding modes. Amongst those hits, 5777208 and 5919607 have been found to have remarkable docking score and binding interactions. Key words:RSK, E-pharmacophore, Cancer, Virtual screening, Docking. E-Farmakofor Haritalanması, Sanal Tarama ve Moleküler Kenetlenmenin Birleştirilmesi ile Etkili ve Seçici P90 Ribosomal S6 Kinaz (RSK) İnhibitörlerinin Belirlenmesip90 Ribozomal kinazlar serin/treonin protein kinaz ailesindendir ve kanser hücrelerinin çoğalmasında rol aldıkları saptanmıştır. Yüksek seçiciliğe sahip inhibiötlerin ve aynı zamanda bu inhibitörlerin mekanizmalarına ait yapısal bilgilerin eksikliği, bu alanda ilerlemeyi kısıtlamaktadır. Uygun bir RSK kristal yapısı olmadan yapılan in siliko protein-inhibitör çalışmalarında da yanlış sonuçlara varıldığı söylenmiştir. Bu çalışmada, yeni çözümlenen, en etkili ve seçici RSK inhibitörlerinden LJH685 ile kompleks halinde olan, yüksek çözünürlükteki RSK2 kristal yapısı kullanılarak, RSK2'ye ait ilk efarmakofor modeli oluşturulmuştur. Büyük veri tabanlarının (144 milyondan fazla konformasyona sahip yaklaşık 7 milyon bileşik) sanal taraması, ardından bir dizi moleküler kenetleme çalışması ve kritik bağlanma modlarının görsel olarak incelenmesi çalışmalarının birleştirilmesi ile 12 bileşik umut vaat eden etkili ve seçici inhibitörler olarak önerilmiştir. Bu bileşikler arasından 5777208 ve 5919607'nin kayda değer kenetlenme skorlarının ve bağlanma etkileşimlerinin olduğu bulunmuştur.

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Insights into the Inhibition of the p90 Ribosomal S6 Kinase (RSK) by the Flavonol Glycoside SL0101 from the 1.5 Å Crystal Structure of the N-Terminal Domain of RSK2 with Bound Inhibitor

Cited by 42 publications

References 93 publications

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer

Synthesis and Evaluation of Novel RSK Inhibitors in a Living Human Breast Model

E-Pharmacophore Mapping Combined with Virtual Screening and Molecular Docking to Identify Potent and Selective Inhibitors of P90 Ribosomal S6 Kinase (RSK)

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