Ono Pharma Foundation Symposium

The Koehler Lab uses chemical biology approaches to investigate deregulated transcriptional programs in cancer. We are taking on the challenge of developing chemical probes that either directly target oncogenic transcription factors (TFs), currently deemed ‘undruggable,’ or that target ‘nearest neighbor’ proteins that indirectly modulate TF function through mechanisms involving alterations in protein production or protein stability. The probes can be used to further understand the functions surrounding any given transcriptional regulator, clarify their relevance as therapeutic targets, and enable credentialing of mechanisms for targeting by small-molecule drugs. As an example of our approach, probes that impact the MYC oncogene, which encodes a master regulator and is causally associated with most human malignancies, will be described.  The lab identified a unique small molecule, KI-MS2-008, that binds to MAX, inhibits MYC-driven transcription, and stabilizes the MAX homodimer in vitroand in cells while reducing MYC protein levels. The compound displays anti-tumor activities in vitro and in vivo using engineered and non-engineered systems.