SHY Therapeutics begins first-in-human trial of novel 19S proteasome inhibitor SHY-ONC6

New York-based biotech SHY Therapeutics has initiated a Phase I first-in-human (FIH) trial of SHY-ONC6, a novel proteasome inhibitor targeting the 19S regulatory particle of the 26S proteasome, in patients with advanced or metastatic solid tumors. The multicenter study, registered as NCT07705334, enrolled its first patient on June 29, 2026, and is recruiting at sites in Denver, Houston, and San Antonio. The asset represents a mechanistic departure from approved proteasome inhibitors, which target the 20S catalytic core rather than the 19S regulatory particle.

The Phase I study consists of two parts: a dose-escalation phase (Phase Ia) using accelerated titration and a Bayesian optimal interval design to identify the maximum tolerated dose, followed by a dose-expansion phase (Phase Ib) in disease-specific cohorts. SHY-ONC6 is administered orally once daily in 21-day cycles. The trial plans to enroll approximately 30 patients aged 18 years or older with advanced or metastatic solid tumors—including triple-negative breast cancer, colorectal cancer, gastric cancer, hepatocellular carcinoma, non-small cell lung cancer, mesothelioma, pancreatic cancer, prostate cancer, and soft tissue sarcoma—whose disease has progressed on, or who are intolerant to, standard therapies. Primary endpoints include determination of the maximum tolerated dose and recommended Phase II dose, as well as assessments of dose-limiting toxicities and adverse events. Secondary endpoints include objective response rate, duration of response, progression-free survival, overall survival, and pharmacokinetic parameters such as area under the plasma concentration-time curve, maximum plasma concentration, and elimination half-life. The trial is expected to complete in May 2028.

Proteasome inhibition is an established therapeutic strategy in oncology, particularly for hematologic malignancies. Approved proteasome inhibitors—including bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro)—target the 20S catalytic core of the 26S proteasome, preventing the degradation of ubiquitinated proteins. The resulting accumulation of damaged and misfolded proteins triggers proteotoxic stress and apoptosis in cancer cells, particularly multiple myeloma and certain lymphomas, which are highly dependent on the proteasome to maintain protein homeostasis. While these agents have transformed treatment for blood cancers, their activity in solid tumors has been more limited due to a combination of biological resistance and dose-limiting toxicities.

SHY-ONC6 takes a different approach by targeting the 19S regulatory particle, which sits upstream of the 20S catalytic core and is responsible for recognizing, unfolding, and delivering ubiquitinated proteins for degradation. The drug selectively inhibits AAA+ ATPase subunits within the 19S complex, aiming to disrupt proteasome function at an earlier stage than existing therapies. Researchers have proposed that targeting the 19S regulatory particle could overcome some mechanisms of resistance to 20S inhibitors and produce a distinct anti-tumor profile, although this approach remains experimental and has yet to be validated in clinical studies.

The company has not disclosed any partnerships or external funding related to the SHY-ONC6 program.

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