Abstract 1291: The novel c-MYC inhibitor IDP-121 exhibits strong anti-myeloma effect
Authors: Krzeminski Patryk , González-Méndez Lorena , Segundo Laura San , Mogollón Pedro , Diaz Andrea , Hernández-García Susana , Algarín Macarena , Martín-Sánchez Montserrat , Cochete Luis , Paino Teresa , Esteban Santiago , Nevola Laura , Gutiérrez Norma C. , Mateos Mª-Victoria , Garayoa Mercedes , Ocio Enrique M. 
Published: July 2021

Abstract
Multiple myeloma (MM) is a blood malignancy having its origin in differentiated B cells.1 The overall survival of MM patients has clearly improved with the use of autologous stem cell transplantation and the more recent introduction of novel therapeutic strategies. However, for the majority of patients, the disease will eventually relapse even after good initial response and remains incurable. The uncontrolled activation of c-Myc due to translocation, mutation or alteration of upstream signalling pathways is a common characteristic of many cancers including MM.2 No compound targeting c-Myc is yet used in the clinic, mostly due to its intra-nuclear location and its intrinsically disordered nature, that renders small molecule or antibody therapy development problematic. Here we describe the anti-myeloma effect of IDP-121, a stapled peptide specifically designed to target c-MYC protein (see Abstract 1). IDP-121 reduced viability of a large set of MM cell lines, with apoptosis as the primary mechanism of cell death. Short contact time was sufficient to exert its anti-myeloma effect reflecting rapid cellular uptake. Similar reduction of cell viability was observed ex vivo by multiparameter flow cytometry in primary cells derived from MM patients. Interestingly, normal lymphocytes from these same patients, were largely preserved from IDP-121-induced apoptosis, suggesting its selectivity and the presence of a therapeutic window. IDP-121 was able to rapidly disrupt the c-MYC/MAX complex in cells as confirmed by immune-precipitation and FRET experiments. The complex disruption was accompanied by the reduction of whole c-MYC protein, probably trigging monomer degradation. No effect on c-Myc gene expression levels was observed, consistent with a direct c-MYC protein inhibitor. IDP-121 exposure led to c-MYC nuclear depletion, with consequent reduction of the binding of the transcription factor complex to DNA. In vivo, IDP-121 shows significant reduction of tumor growth in a subcutaneous plasmacytoma and a disseminated xenograft model of MM. The HPLC-MS and IHC analyses of tumor tissue after treatment confirms effective tumoral tissue distribution and target engagement, with significant reduction of c-MYC protein and cell proliferation in vivo. Finally, and importantly, preliminary combination experiments highlight that IDP-121 potentiated the activity of MM standards of care such as bortezomib and dexamethasone. The results presented here suggest that IDP-121 could be a first-in-class inhibitor of c-MYC in MM. The drug-like properties and efficacy also in solid tumors of IDP-121 have been demonstrated in vivo (see Abstracts 3). In addition, IDP-121 has progressed through GLP toxicology studies without evidence of major systemic toxicity, allowing for the first viable Myc-targeted therapy to enter Phase 1 clinical trials in 2021.
1Bergsagel PL, et al. J Am Soc Clin Oncol. 2005; 23:6333–8.2Holien T., et al. Blood. 2012; 120: 2450–3.
Citation Format: Patryk Krzeminski, Lorena González-Méndez, Laura San Segundo, Pedro Mogollón, Andrea Diaz, Susana Hernández-García, Macarena Algarín, Montserrat Martín-Sánchez, Luis Cochete, Teresa Paino, Santiago Esteban, Laura Nevola, Norma C. Gutiérrez, Mª-Victoria Mateos, Mercedes Garayoa, Enrique M. Ocio. The novel c-MYC inhibitor IDP-121 exhibits strong anti-myeloma effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1291.