Abstract 2471: IDP-121, a first in class staple peptide targeting c-MYC

Abstract

MYC is a transcription factor involved in fundamental cellular functions such as proliferation, apoptosis, differentiation, metabolism and, as lately discovered, immune response. [1,2] It is deregulated in a wide variety of aggressive human cancers and its overexpression is one of the most common events associated with tumorigenesis, making it one of the most attractive yet challenging targets in oncology.[3] c-MYC protein structure is mostly disordered in its monomeric state, and assumes a helix-loop-helix fold upon binding to its protein partner MAX. The absence of clefts or hydrophobic pockets (typical of enzymes) and the large protein-protein interaction surface formed in the c-MYC/MAX complex represent a challenge for the design of small molecule inhibitors. Moreover, the intra-nuclear localization of c-MYC renders the use of antibodies impossible. Hence, it is not surprising that conventional drug development has failed and no therapeutic has yet progressed into clinical trials.[4] Here we describe IDP-121, a stapled peptide specifically designed to target c-MYC protein. A library based on c, l, n-MYC and MAX druggable regions was designed, with a bias towards disruption of c-MYC (residual) intra-protein interactions. The primary goal in the initial screen was to identify compounds able to block c-MYC's fold-like state that allows binding to MAX. A functional (cellular) assay was used for our screening program to ensure cell and nuclear penetration. Stapling technology was implemented to overcome the lack of stability and cell permeability common to unmodified peptides, whilst retaining c-MYC specificity and a large surface coverage. The lead compound, IDP-121, is stable to proteolysis and is rapidly internalized into cells, distributing efficiently into the nucleus (see Abstract 3). The interaction with c-MYC was characterized by HSQC-NMR, Fluorescence Polarization (FP) and Surface Plasmon Resonance (SPR). IDP-121 binds specifically to c-MYC, with a Kd of 400 nM, an affinity ten-fold higher than c-MYC/MAX interaction, allowing IDP-121 to displace MAX from the binding site. SAR studies were conducted to tailor the elements essential for its biological function. Isolated protein complex (ELISA), and pull-down and FRET experiments confirmed disruption of the c-MYC/MAX complex by IDP-121 (see Abstracts 2). The drug-like properties and efficacy in hematological and solid tumors of IDP-121 have been demonstrated in vivo (see Abstracts 2 and 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. 1.Casey S.C. et al. Science 2016; 352 (6282): 227–231 2.Casey S.C. et al. Blood 2018; 131 (18): 2007-20153.Dang CV. Cell. 2012;149(1):22-35.4. Whitfield J. R., Front. Cell Dev. Biol. 2017 Citation Format: Carmen Calvis, Andreas Beier, Michael Feichtinger, Theresa Höfurthner, Miguel Moreno, Ramon Messeguer, Robert Konrat, Santiago Esteban, Laura Nevola. IDP-121, a first in class staple peptide targeting c-MYC [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 2471.

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

“…However, c-Myc is an intrinsically disordered protein (IDP), therefore the expanded unstructured surface of the bHLHZip domain is deficient in deep hydrophobic pockets that are essential for typical small-molecule targeting strategies, and the nuclear localization of endogenous c-Myc is another restriction for therapeutic agents. 182,183 The above reasons have resulted in the authentication of inhibitors primarily via high-throughput screening (HTS) of chemical libraries rather than traditional structure-based design. 184 Yet so far, due to insufficient druggability probably, no small-molecule inhibitors of c-Myc/Max PPI have been tested in clinical trials.…”

“…Hence, developing inhibitors of the PPI between c‐Myc and Max to impede the transcription of oncogenes represents a promising approach for cancer therapy. However, c‐Myc is an intrinsically disordered protein (IDP), therefore the expanded unstructured surface of the bHLHZip domain is deficient in deep hydrophobic pockets that are essential for typical small‐molecule targeting strategies, and the nuclear localization of endogenous c‐Myc is another restriction for therapeutic agents 182,183 . The above reasons have resulted in the authentication of inhibitors primarily via high‐throughput screening (HTS) of chemical libraries rather than traditional structure‐based design 184 .…”