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.

Belharra’s platform discovers novel, functionally relevant binding pockets on elusive, high-value drug targets across the undrugged proteome and can reveal binding pockets, in any protein or protein complex, in any cell type.  This talk will focus on the discovery of chemical probes and ligandable pockets across transcription factors.    

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.