Transcription factors (TFs) control gene expression by recognizing specific DNA sequences, thereby regulating most, if not all, aspects of cellular function. As such, many cancers are hallmarked by deregulation of TFs, which makes them ideal targets for cancer therapy. However, direct inhibition of the DNA binding of TFs remains largely untapped due to technical challenges in targeting protein-protein and protein-DNA interactions. In particular, c-Myc, a protooncogenic TF of the basic helix-loop-helix family, is deregulated in up to 70% of cancers but its inhibitor development has eluded researchers for decades. Here we developed a modular platform to create fully synthetic miniproteins derived from bHLH TFs. As a proof-of-concept study, synthesis of heterodimeric, stabilized DNA-binding helices derived from Myc/Max yielded synthetic DNA-binding domains (sDBDs) that recapitulate the DNA binding activity of full-length TFs. Lead sDBDs showed increased structural stability, cellular uptake, and promising intracellular target accessibility. Extensive studies into the stabilization of secondary and tertiary structures provided insights into their structure activity relationship, and further optimizations of sDBDs led to the development of new orthogonal chemistries. Next, we applied the synthetic platform to a synthetic transcription factor (STF) scaffold derived from the basic and leucine zipper domains of Max. STFs showed superior binding affinity and specificity to target DNA, and effectively competed with bHLH proteins in vitro. Vigilant stabilization of secondary, tertiary and quaternary structural elements in STFs simultaneously preserved biochemical activity and significantly improved structural, thermal and proteolytic stability. Lead STFs are cell permeable, distribute throughout the cytosol and nucleus intact, and directly bind Myc target genes. We also solved the crystal structure of an STF-DNA complex, confirming that STFs assemble and recognize DNA in a manner similar to full length bHLH TFs. Finally, we conducted thorough studies into the synthesis of dimeric STFs (dSTFs) using the multidimensional orthogonal chemistries in our platform. dSTFs possess enhanced activity and stability compared to STFs, and represent the largest stabilized miniprotein that have been made to date. Collectively, these results validated the modularity and robustness of our synthetic platform, and multiple functional miniproteins from the platform, enabling the development of new solutions for every unique TF. Additionally, lead functional miniproteins that have emerged from our screens, possess great potentials for direct inhibition of Myc DNA binding, representing a critical first step towards overcoming the grand challenge of targeting Myc.