David J. Tweardy, Welch Chair in Chemistry at the University of Texas MD Anderson Cancer Center, specializes in identifying the structural and biochemical features of signaling proteins and oncoproteins that render them susceptible to modulation by small molecules for disease treatment. Over two decades, his groundbreaking work on cytokine signaling and especially the STAT3 protein has deepened scientific understanding of intracellular signaling and led to promising therapeutic candidates now in clinical trials.
STAT3, a member of the signal transducer and activator of transcription (STAT) protein family, plays a vital role in transmitting signals from cytokines to the cell nucleus, where it regulates gene expression. STAT3 is critical in cytokine signaling and also plays a role in inflammation and cell survival. Dr. Tweardy’s early discoveries highlighted the efficiency of STAT3’s recruitment to activated receptors.
“As a biochemist, I was very interested in how a region on STAT3 allows for its recruitment to the activated receptor at the atomic level. In one fell swoop, you spark a pretty complicated cascade of signaling events. That became this long, long pathway to understand the molecular interactions.”
Since STAT3 is ubiquitous and essential for embryonic development, genetic “knockout” experiments proved impractical for studying its functions. Instead, Dr. Tweardy turned to chemical genetics to selectively inhibit STAT3 in adult mice. This approach, while challenging, enabled his team to identify a novel small-molecule inhibitor capable of disrupting STAT3’s function without genetic manipulation.
Dr. Tweardy and his team analyzed STAT3’s phosphopeptide-binding domain using a structure-based approach, leveraging computational docking experiments to screen almost one million potential compounds. They discovered a novel STAT3 inhibitor, which is now in Phase II clinical trials for liver cancer and idiopathic pulmonary fibrosis (IPF).
“We started docking small molecules into a peptide-binding pocket that was very distinct and separate from anybody else’s. And it turns out, in virtually every model where STAT3 was critical for the pathogenesis, our molecule to target it worked.”
If successful, the drug will be the first small-molecule inhibitor targeting an Src-homology (SH) 2 domain to reach clinical application. The implications extend beyond STAT3, opening new avenues for targeting other SH2 domain–containing proteins, which play roles in numerous diseases. The ultimate goal is to develop a broader class of inhibitors that could be applied across multiple disease contexts, including cancer and inflammatory diseases.
In other new projects, Dr. Tweardy continues to drive innovation in drug discovery by blending molecular biology, chemistry and artificial intelligence (AI). Dr. Tweardy and his team are utilizing AI-driven modeling techniques to predict and optimize drug interactions at an atomic level. By incorporating AI into their structural analysis, they aim to accelerate the identification of new drug candidates and improve the efficiency of small-molecule design.
“With Welch support, we can look at different SH2 domain–containing proteins that are biologically important in disease. If we focus on the atomic-level interaction and have a really good structure [of the protein] developing, then we can establish what small-molecule compounds might effectively interfere with that interaction. We’re really excited that we may be able to fill this gap using AI.”
As his STAT3 inhibitor progresses through clinical trials and his team expands their AI-driven drug discovery efforts, Dr. Tweardy continues to push the boundaries of what is possible in biochemistry and medicine.