Aiming at an ‘Undruggable” target, Pyrotech’s class 1 small-molecule candidate gets approved for sepsis clinical trials
On August 4, Pyrotech Therapeutics (“Pyrotech”) announced that its independently developed small-molecule pyroptosis inhibitor, PTT-121, has been approved for clinical trials in China, intended for the treatment of sepsis and septic shock. This is a specific GSDMD inhibitor, and the GSDMD target was previously considered “undruggable”.
Pyroptosis is a programmed cell death mediated by the gasdermin protein. In 2015, the team led by Feng Shao at the Beijing Institute of Life Sciences published groundbreaking findings in Nature, confirming that GSDMD is the direct executor protein of pyroptosis, redefining the core mechanism of pyroptosis at the molecular level, and opening up a novel path to drug development for many inflammation-related diseases.
Sepsis is a fatal organ dysfunction caused by a dysregulated response to infection. The disease progresses extremely rapidly, often triggering a systemic cytokine storm, septic shock, and multiple organ failure within hours, making it a typical ICU emergency. Increasing clinical evidence suggests that GSDMD-mediated pyroptosis plays a crucial role in the development and progression of sepsis.
GSDMD is a novel membrane-perforating protein, and there are currently no precedents for drug development targeting membrane-perforating proteins or any applicable drug development pathways. Furthermore, GSDMD lacks any enzymatic activity and traditional small-molecule binding pockets; thus, it is generally considered an “undrugable” target.
Relying on the original research of Dr Shao’s laboratory and leveraging its unique drug development platform, Pyrotech’s R&D team has successfully developed a highly specific, highly active, and intravenously administered small-molecule inhibitor of GSDMD, PTT-121. Preclinical data show that PTT-121 exhibits good efficacy in various sepsis disease models, effectively inhibiting cytokine storms and significantly reducing the risk of death in animal models.
Source: Pyrotech Therapeutics | Top Image: Upsplash
