Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc

Abstract

c-Myc is a transcription factor that is constitutively and aberrantly expressed in over 70% of human cancers. Its direct inhibition has been shown to trigger rapid tumor regression in mice with only mild and fully reversible side effects, suggesting this to be a viable therapeutic strategy. Here we reassess the challenges of directly targeting c-Myc, evaluate lessons learned from current inhibitors, and explore how future strategies such as miniaturisation of Omomyc and targeting E-box binding could facilitate translation of c-Myc inhibitors into the clinic.

Keywords: Leucine zipper; Oncogene; Peptide; Protein-protein interaction; Transcription.

Fig. 1

The structure and interaction partners of c-Myc. a Crystal structure of the c-Myc/Max dimer bound to E-box DNA (PDB ID 1NKP) [2]. b Scheme showing activating and repressing interaction partners, represented by double headed arrows, within the Myc/Max/Mxd network [3, 4]. c Different regions of c-Myc protein, including the MYC boxes (0, I, II, IIIa, IIIb, IV), Nuclear Localization Sequence (NLS) and bHLHZip domain along with the binding sites of its key interaction partners [–10]

Fig. 2

Small molecule inhibitors of c-Myc. a IIA6B17 [73]. b 10058-F4 [76]. c Evolution of 10074-G5 [85]. d Evolution of Mycro1 and Mycro2 [88]. e MYCMI-6 [91]. f Evolution of MYCi [94]. g KJ-Pyr-9 [62]

Fig. 3

Proposed mechanisms of Omomyc. Studies have suggested that: 1. Omomyc (Orange) homodimer blocks c-Myc/Max dimer from binding to E-box DNA (Red). 2. Omomyc binds to Max (Green), sequestering Max from c-Myc (Blue) and 3. In the presence of Omomyc, c-Myc levels are reduced due to proteasomal degradation, a process potentially tiggered by 2 [49, 105].

Fig. 4

Overview of peptides and proteins that inhibit c-Myc, including E-box binding inhibitors (Omomyc, Max, ME47, Mxd and linked basic helices), inhibitors of c-Myc/Max binding (Omomyc, Max, Mxd, Monoclonal antibody, H1 peptide, a Max/aMip) and a c-Myc degradation promoter (Omomyc). Proteins marked with (*) are shown in their dimeric form [5, 99, 106, 107, 111, 112, 118, 120, 123]