A novel inhibitor L755507 efficiently blocks c-Myc–MAX heterodimerization and induces apoptosis in cancer cells

Ashutosh Singh,Ankur Kumar,Prateek Kumar,Namyashree Nayak,Taniya Bhardwaj,Rajanish Giri,Neha Garg

doi:10.1016/j.jbc.2021.100903

Ashutosh Singh, Ankur Kumar + Show 5 more

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c-Myc is a transcription factor that plays a crucial role in cellular homeostasis, and its deregulation is associated with highly aggressive and chemotherapy-resistant cancers. After binding with partner MAX, the c-Myc–MAX heterodimer regulates the expression of several genes, leading to an oncogenic phenotype. Although considered a crucial therapeutic target, no clinically approved c-Myc-targeted therapy has yet been discovered. Here, we report the discovery via computer-aided drug discovery of a small molecule, L755507, which functions as a c-Myc inhibitor to efficiently restrict the growth of diverse Myc-expressing cells with low micromolar IC50 values. L755507 successfully disrupts the c-Myc–MAX heterodimer, resulting in decreased expression of c-Myc target genes. Spectroscopic and computational experiments demonstrated that L755507 binds to the c-Myc peptide and thereby stabilizes the helix–loop–helix conformation of the c-Myc transcription factor. Taken together, this study suggests that L755507 effectively inhibits the c-Myc–MAX heterodimerization and may be used for further optimization to develop a c-Myc-targeted antineoplastic drug.

Highlights

The protooncogene c-myc, a basic helix–loop–helix leucine zipper transcription factor, is involved in the regulation of multiple cellular functions including cell growth, proliferation, and apoptosis, while blocking the differentiation [1]
The crystal structure of Myc–MAX heterodimer bound to DNA (Protein Data Bank [PDB] ID: 1NKP [26]) was selected to identify a plausible binding site for bioactive molecules
Myc–MAX interaction is among them, which binds to the E-box sequence at the target gene promoter and is responsible for the oncogenic phenotype [6, 7]

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Introduction

The protooncogene c-myc (referred to here as Myc), a basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factor, is involved in the regulation of multiple cellular functions including cell growth, proliferation, and apoptosis, while blocking the differentiation [1]. All three cell lines showed Myc’s endogenous expression at the mRNA and protein level, as depicted from qPCR and Western blot data (Fig. S5, B and C). The reported Myc inhibitor, that is, 10074-G5, showed cell inhibition in a dosedependent manner, but interestingly, the obtained IC50 value was found to be higher than L755507 for the studied cell lines.

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