Abstract 1615: NMS-812, a novel potent PERK inhibitor that also inhibits GCN2, exhibits strong anti-tumor activity as single agent and in combination in preclinical models
Authors: Perrera Claudia , Pulici Maurizio , Banfi Patrizia , Avanzi Nilla , Carenzi Davide , Casero Daniele , Ciavolella Antonella , Gianellini Laura , Gasparri Fabio , Saturno Grazia , Valsasina Barbara , Ardini Elena , Montagnoli Alessia , Galvani Arturo P. , Isacchi Antonella 
Published: April 2023

PERK and GCN2 are eIF-2α serine-threonine kinases activated by endoplasmic reticulum (ER) stress and amino acid deprivation respectively. These kinases are key effectors of the unfolded protein response (UPR) and amino acid Response (AAR) branches of the integrated stress response (ISR). ISR downregulates protein synthesis while upregulating specific genes in response to various cellular stresses, thus allowing adaptation and survival. PERK and GCN2 cooperate to modulate survival under stress conditions in cancer cells, with GCN2 activation compensating when PERK is inhibited, therefore suggesting a certain degree of redundancy between the two. Multiple myeloma (MM) and other protein-secreting tumors are highly dependent on UPR for survival, due to their high protein load. Therefore, PERK inhibition represents a promising anticancer approach in these tumor types. Notably, in these contexts, dual PERK/GCN2 inhibition may be more effective than inhibiting the single kinase.NMS-03597812 is a novel, very potent, ATP-competitive PERK/GCN2 inhibitor, NMS-812 is preferentially active in vitro on multiple myeloma cell lines; activity has however been observed also on lymphoma and selected solid tumor cell lines, suggesting a broader but still specific role of PERK and GCN2 inhibition depending on cell context. In assays revealing the mechanism of action, as expected, a transient dose-dependent eIF2α pathway activation is observed, suggesting the attempt of GCN2 to compensate for PERK inhibition. However, at higher doses, NMS-812 strongly induces pathway downmodulation and apoptosis compared to prototype PERK selective inhibitors. NMS-812 treatment of a MM xenograft model significantly prolongs the median survival time as single agent and demonstrates synergistic activity with MM standard of care (SOC) agents. In lymphoma, NMS-812 shows activity both as single agent and in combination with SOC.NMS-812 shows a favorable in vitro ADME profile and good PK properties with oral bioavailability in preclinical species and an acceptable toxicity profile. NMS-812 is a novel dual, PERK/GCN2 inhibitor with potential for first-in-class, that validates dual PERK and GCN2 inhibition as a therapeutic approach for MM and other PERK/GCN2-dependent settings. Based on these promising results, a Ph1 study has been started in Multiple Myeloma with plans to expand to other malignancies in the near future.

Citation Format: Claudia Perrera, Maurizio Pulici, Patrizia Banfi, Nilla Avanzi, Davide Carenzi, Daniele Casero, Antonella Ciavolella, Laura Gianellini, Fabio Gasparri, Grazia Saturno, Barbara Valsasina, Elena Ardini, Alessia Montagnoli, Arturo P. Galvani, Antonella Isacchi. NMS-812, a novel potent PERK inhibitor that also inhibits GCN2, exhibits strong anti-tumor activity as single agent and in combination in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1615.