Therapeutic Interventions of Cancers Using Intrinsically Disordered Proteins as Drug Targets: c-Myc as Model System

Abstract

The concept of protein intrinsic disorder has taken the driving seat to understand regulatory proteins in general. Reports suggest that in mammals nearly 75% of signalling proteins contain long disordered regions with greater than 30 amino acid residues. Therefore, intrinsically disordered proteins (IDPs) have been implicated in several human diseases and should be considered as potential novel drug targets. Moreover, intrinsic disorder provides a huge multifunctional capability to hub proteins such as c-Myc and p53. c-Myc is the hot spot for understanding and developing therapeutics against cancers and cancer stem cells. Our past understanding is mainly based on in vitro and in vivo experiments conducted using c-Myc as whole protein. Using the reductionist approach, c-Myc oncoprotein has been divided into structured and disordered domains. A wealth of data is available dealing with the structured perspectives of c-Myc, but understanding c-Myc in terms of disordered domains has just begun. Disorderness provides enormous flexibility to proteins in general for binding to numerous partners. Here, we have reviewed the current progress on understanding c-Myc using the emerging concept of IDPs.

Keywords: Intrinsically disordered proteins; and molecular recognition elements; conformational ensembles; therapeutics and drug development; transcription factors.

Figure 1.

Domain architecture of c-Myc protein and the interacting partners’ network. This figure shows that c-Myc protein residues have different functional characteristics: N-terminal region serves as transactivation domain (TAD) by performing multiple interactions with several interacting partners and C-terminal region forms heterodimer with MAX protein that ultimately performs DNA binding activities. These 2 regions are further divided into small motifs: MB1 (Myc Box 1) and MB2 (Myc Box 2) present in TAD domain (N-terminal) and BHLH (basic helix-loop-helix) and LZ (leucine zipper) present at C-terminal. NLS, Nuclear localization Signal or Sequence.

Figure 2.

Various drug development strategies showing the origin of disorder-based drug targeting. (A) This cartoon represents the conventional method of structure-based drug design and targeting catalytic active site of structured proteins using small inhibitor molecules (black inhibitor molecule shown here is just symbolic). (B) This shows the strategy to inhibit protein-protein interactions between disordered protein (blue) and its interacting partner (grey) by the inhibitor molecule (black symbolic) that can bind to the ordered structure of interacting partner. (C) This figure shows the stabilizing function of small-molecule inhibitor which binds to ensemble states of disordered proteins in different conformations and inhibits the functional ability. IDPs indicate intrinsically disordered proteins. Reproduced with permission from Jin et al (2013), representing the complex formation between conformational ensembles of c-Myc_370-409/10074-A4 inhibitor molecule using molecular dynamic simulations).

Figure 3.

Myc:Max dimer–associated peptidomimetic and small-molecule inhibitors. This figure represents the C-terminal disordered loop (purple enlarged in circle) in leucine zipper of c-Myc that has been targeted by peptidomimetic compound inhibitors, such as IIA6B17 and IIA4B20, and their analogues, mycmycin-1 and mycmycin-2. In addition, further effective small-molecule inhibitors, such as 10058-F4, 10074-G5, PKUMDL-YC-1101, PKUMDL-YC-1201, PKUMDL-YC-1202, PKUMDL-YC-1203, PKUMDL-YC-1204, PKUMDL-YC-1205, and PKUMDL-YC-1301, were also developed to inhibit Myc:Max dimer formation.