Linked Bivalent Small Molecule Inhibitors for Inhibiting c-Myc-Driven Tumor Growth
The field of oncology extensively studies transcription factors like c-Myc, which are critical regulators of cell growth and survival. c-Myc is frequently overexpressed or deregulated in numerous human cancers. Its aberrant activity drives tumor progression and is strongly correlated with poor patient prognosis. Therefore, there is a significant unmet medical need to develop effective therapeutic strategies that specifically target the oncogenic functions of c-Myc to inhibit cancer cell proliferation and improve patient outcomes.Despite the clear need, directly targeting c-Myc has proven exceptionally challenging. Its intrinsically disordered nature and lack of enzymatic activity make it difficult to identify suitable binding pockets for drug development. Prior therapeutic approaches, such as antisense oligonucleotides or indirect inhibition of downstream targets, have encountered significant limitations, including issues with drug delivery, off-target effects, and compensatory cellular pathways leading to redundancy. Furthermore, earlier attempts to develop small molecule inhibitors specifically designed to disrupt the crucial c-Myc-Max heterodimerization, a key step in c-Myc's oncogenic function, have generally suffered from insufficient potency, often requiring high concentrations for minimal effect.
Description
This technology introduces linked bivalent small molecule inhibitors designed to disrupt the critical association between the oncogenic transcription factor c-Myc and its partner Max. These compounds feature two distinct c-Myc binding moieties, A and B, joined by a flexible chemical linker. Moieties A and B simultaneously bind to two different sites on the intrinsically disordered basic-helix-loop-helix-leucine-zipper (bHLH-Zip) domain of c-Myc. This dual engagement achieves synergistic, high-affinity inhibition of the c-Myc-Max interaction, consequently inhibiting c-Myc-driven tumor cell growth. The key differentiation lies in its bivalent design, addressing the long-standing challenge of targeting c-Myc due to its disordered nature and lack of enzymatic activity. Unlike previous monovalent inhibitors that exhibited low potency, these compounds leverage simultaneous engagement of two binding sites. This results in a synergistic enhancement of binding affinity by over three orders of magnitude, achieving low nanomolar dissociation constants. This significantly improved potency enables effective disruption of c-Myc-Max DNA binding and selective inhibition of c-Myc-dependent cancer cells at much lower, therapeutically relevant concentrations.Applications
- Targeted cancer therapy- c-Myc inhibitor drug
- Oncology therapeutic agent
- Anti-tumor growth agent
- Novel drug compound development
Advantages
- Achieves synergistic, high-affinity inhibition of the oncogenic c-Myc-Max interaction.- Effectively inhibits c-Myc-driven tumor cell growth.
- Provides a novel and promising therapeutic strategy for c-Myc-driven cancers, a previously challenging target.
- Demonstrates selective targeting of c-Myc-dependent cancer cells with reduced toxicity to healthy cells.