Directly Suppressing MYC Function with Novel Alkynyl-Substituted Phenylpyrazole Derivatives that Induce Protein Degradation and Perturb MYC/MAX Interaction

Despite being a highly sought-after therapeutic target
for human
malignancies, myelocytomatosis viral oncogene homologue (MYC) has
been considered intractable due to its intrinsically disordered nature,
making the discovery of in vivo effective inhibitors that directly
block its function challenging. Herein, we report structurally novel
alkynyl-substituted phenylpyrazole derivatives directly perturbing
MYC function. Among them, compound 37 exhibited superior
antiproliferative activities to those of MYCi975 against multiple
malignant cell lines. It induced dose-dependent MYC degradation in
cells with degradation observed at the concentration as low as 1.0
μM. Meanwhile, its direct suppression of MYC function was confirmed
by the capability to inhibit the binding of MYC/MYC-associated protein
X (MAX) heterodimer to DNA consensus sequence, induce MYC thermal
instability, and disturb MYC/MAX interaction. Moreover, 37 demonstrated enhanced therapeutic efficacy over MYCi975 in a mouse
allograft model of prostate cancer. Overall, 37 deserves
further development for exploring MYC-targeting cancer therapeutics.