Directly Suppressing MYC Function with Novel Alkynyl-Substituted Phenylpyrazole Derivatives that Induce Protein...

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• The myelocytomatosis viral oncogene homologue (MYC) is a critical oncogene and a highly sought-after target for cancer therapeutics.
• MYC's intrinsically disordered nature presents significant challenges for developing effective inhibitors that directly block its function in vivo.
• Existing MYC inhibitors often face limitations in efficacy and direct functional perturbation.

Purpose of the Study:

• To design and synthesize novel alkynyl-substituted phenylpyrazole derivatives as direct MYC function inhibitors.
• To evaluate the antiproliferative activity and MYC-targeting mechanisms of these novel compounds.
• To compare the therapeutic efficacy of the lead compound against a known MYC inhibitor in preclinical cancer models.

Main Methods:

• Synthesis of novel alkynyl-substituted phenylpyrazole derivatives.
• Assessment of antiproliferative activity in multiple malignant cell lines.
• Evaluation of MYC degradation, MYC/MAX binding inhibition, MYC thermal instability, and MYC/MAX interaction disruption.
• In vivo efficacy testing in a mouse allograft model of prostate cancer.

Main Results:

• Compound 37 demonstrated superior antiproliferative activity compared to MYCi975 across various cancer cell lines.
• Compound 37 induced dose-dependent MYC degradation at concentrations as low as 1.0 μM.
• Direct suppression of MYC function by compound 37 was confirmed through inhibition of MYC/MAX binding to DNA, induction of MYC thermal instability, and disruption of MYC/MAX interaction.
• Compound 37 exhibited enhanced therapeutic efficacy over MYCi975 in a preclinical prostate cancer model.

Conclusions:

• Novel alkynyl-substituted phenylpyrazole derivatives, particularly compound 37, effectively perturb MYC function.
• Compound 37 represents a promising candidate for further development as a MYC-targeting cancer therapeutic.
• The findings support the potential of targeting MYC degradation for effective cancer treatment.