We determined that LZK (encoded by MAP3K13) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified MAP3K13. A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules. Inhibition of LZK catalytic activity suppressed tumor growth in HNSCC PDX models with amplified MAP3K13. We designed proteolysis-targeting chimeras (PROTACs) and demonstrate that our lead PROTAC promotes LZK degradation and suppresses expression of GOF p53 and c-MYC, leading to impaired viability of HNSCC.

Using our TF-Scan proteomics platform, we identified small-molecule modulators of transcription factors in prostate cancer and chordoma, including covalent inhibitors of NONO that disrupt AR/ARv7-driven transcription in CRPC and compounds targeting TBXT/Brachyury in chordoma. These modulators reduced chromatin occupancy, altered oncogenic transcriptional programs, and revealed new vulnerabilities in historically undruggable TFs, demonstrating a generalizable strategy for transcription factor–directed cancer therapeutics.

Following a computational and biophysical approach, we have discovered a first-in-class series of small molecules that allosterically activate TET2, a master epigenetic regulator enzyme that reprograms tumor cells by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), ultimately leading to tumor cell death. Specifically, ONR-001 exhibits an optimal pharmacokinetic profile, high potency, and good tolerability in rodents. TET2 activation by ONR-001 resulted in strong antitumoral effects in melanoma and CRC models.

We present structural assessments of the minimal binding domains of zinc finger-based transcription factors IKZF2, WIZ and counter target SALL4 revealing that each of these zinc finger-based proteins interacts with cereblon:glue complexes in a unique manner. We explore molecular glue complexes with these neosubstrates and provide a rationale for selective binding and a lack of binding to key counter targets including GSPT1.

Dysregulation within the interaction between pioneer transcription factors and mSWI/SNF(BAF) has been increasingly implicated in oncogenesis. Here, we characterize the direct interaction between BAF and the TF PU.1 via biochemical studies to map the BAF-PU.1 binding site. We present the first high-resolution structure of a human TF–BAF complex as well as potential small molecule inhibitors of this PPI, opening a therapeutic avenue for targeting aberrant TF-BAF activity in cancer.