Author: Wohlfarth, Jonas ; Sinnberg, Tobias ; Niessner, Heike ; Schilling, Bastian ; Schrama, David ; Kosnopfel, Corinna ; Wendlinger, Simone ; Siedel, Claudia ; Jayanthan, Aarthi ; Dunn, Sandra E ; Lenz, Georg ; Schittek, Birgit ; Berthold, Marion ; Siewert, Johannes ; Hofmann, Angelika ; Sauer, Birgit

BACKGROUNDThe mitogen-activated protein kinase (MAPK) signaling pathway is frequently hyperactivated in malignant melanoma and its inhibition has proved to be an efficient treatment option for cases harboring BRAF^V600 mutations (BRAF^Mut). However, there is still a significant need for effective targeted therapies for patients with other melanoma subgroups characterized by constitutive MAPK activation, such as tumors with NRAS or NF-1 alterations (NRAS^Mut, NF-1^LOF), as well as for patients with MAPK pathway inhibitor-resistant BRAF^Mut melanomas, which commonly exhibit a reactivation of this pathway. p90 ribosomal S6 kinases (RSKs) represent central effectors of MAPK signaling, regulating cell cycle progression and survival.METHODSRSK activity and the functional effects of its inhibition by specific small molecule inhibitors were investigated in established melanoma cell lines and patient-derived short-term cultures from different MAPK pathway-hyperactivated genomic subgroups (NRAS^Mut, BRAF^Mut, NF-1^LOF). Real-time qPCR, immunoblots and flow cytometric cell surface staining were used to explore the molecular changes following RSK inhibition. The effect on melanoma cell growth was evaluated by various two- and three-dimensional in vitro assays as well as with melanoma xenograft mouse models. Co-cultures with gp100- or Melan-A-specific cytotoxic T cells were used to assess immunogenicity of melanoma cells and associated T-cell responses.RESULTSIn line with elevated activity of the MAPK/RSK signaling axis, growth and survival of not only BRAF^Mut but also NRAS^Mut and NF-1^LOF melanoma cells were significantly impaired by RSK inhibitors. Intriguingly, RSK inhibition was particularly effective in three-dimensional growth settings with long-term chronic drug exposure and suppressed tumor cell growth of in vivo melanoma models. Additionally, our study revealed that RSK inhibition simultaneously promoted differentiation and immunogenicity of the tumor cells leading to enhanced T-cell activation and melanoma cell killing.CONCLUSIONSCollectively, RSK inhibitors exhibited both multi-layered anti-tumor efficacy and broad applicability across different genomic melanoma subgroups. RSK inhibition may therefore represent a promising novel therapeutic strategy for malignant melanoma with hyperactivated MAPK signaling.

01 Mar 2023·Molecular Therapy - Oncolytics

A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase

Article

Author: Schürer, Stephan C ; Kelley, Tanya T ; Diluvio, Giulia ; Capobianco, Anthony J ; Kolb, Ellen M ; Lahiry, Mohini ; Shersher, Elena ; Astudillo, Luisana ; Alvarez-Trotta, Annamil ; Kovall, Rhett A

Notch activation complex kinase (NACK) is a component of the Notch transcriptional machinery critical for the Notch-mediated tumorigenesis. However, the mechanism through which NACK regulates Notch-mediated transcription is not well understood. Here, we demonstrate that NACK binds and hydrolyzes ATP and that only ATP-bound NACK can bind to the Notch ternary complex (NTC). Considering this, we sought to identify inhibitors of this ATP-dependent function and, using computational pipelines, discovered the first small-molecule inhibitor of NACK, Z271-0326, that directly blocks the activity of Notch-mediated transcription and shows potent antineoplastic activity in PDX mouse models. In conclusion, we have discovered the first inhibitor that holds promise for the efficacious treatment of Notch-driven cancers by blocking the Notch activity downstream of the NTC.

28 Apr 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Q1 · MEDICINE

Article

Author: Fuentes, Pedro ; Borrell, José I. ; Ramón y Cajal, Santiago ; Suarez-Cabrera, Leticia ; Bou-Petit, Elisabeth ; Cano-Galietero, Marta ; Estrada-Tejedor, Roger ; Guijarro, Pedro J. ; Slobodnyuk, Konstantin ; Santamaria, Anna ; Hümmer, Stefan ; Muñoz, María José ; Alarcon, Helena

Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4-b]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	StemSynergy Therapeutics, Inc.	17 Oct 2024

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