Technical Articles

The development history of KRAS inhibitors spans over thirty years, with the first two decades nearly stagnant and the last decade witnessing an explosion. The turning point lies in the new understanding of KRAS's dynamic conformations and advancements in chemical technologies—particularly the application of covalent chemistry, fragment-based drug design, and targeted protein degradation.

ITK is a core non-receptor tyrosine kinase in the T cell receptor signaling pathway, playing a regulatory role in T cell subset differentiation by controlling PLCγ1 activation and calcium signal intensity.

Targeted protein degradation technology has become a key research direction in the field of chemical biology. Among these, PROTAC technology achieves selective degradation of specific proteins by inducing interactions between the target protein and E3 ubiquitin ligase.

Signal transducer and activator of transcription 6 is a key member of the JAK-STAT signaling pathway family, serving as a central effector for interleukin-4 and interleukin-13 signaling, and plays a decisive role in allergic responses, parasitic immunity, and shaping specific tumor microenvironments.

TR-FRET Technology Empowers PROTAC/Molecular Glue Research

PDE4B, a subtype of the phosphodiesterase 4 (PDE4) family, has the core function of specifically hydrolyzing the intracellular second messenger cyclic adenosine monophosphate (cAMP). By regulating cAMP levels, it influences physiological processes such as inflammatory responses and immune activation, making it a key target for inflammatory and neurological diseases. Nerandomilast (BI 1015550), a selective PDE4 inhibitor in the clinical stage, has a clearly defined molecular mechanism of action targeting PDE4B: by binding to the catalytic domain of PDE4B, it competitively inhibits the enzyme's hydrolytic activity toward cAMP, increases intracellular cAMP concentration, subsequently activates the protein kinase A (PKA) signaling pathway, and inhibits the release of pro-inflammatory cytokines (such as IL-6, TNF-α) and the activation of inflammatory cells (such as macrophages, T cells).

In recent years, the field of biomedicine has witnessed a technological revolution—the development of new drug research and development technologies based on protein degradation-targeting chimeras (PROTACs). PROTACs guide the ubiquitin-proteasome system (UPS) within cells to degrade specific target proteins, enabling precise regulation of disease-related proteins. This mechanism not only breaks through the limitations of traditional small-molecule drugs but also brings new hope for "undruggable" targets.

In recent years, the innovative drug development technology based on Proteolysis-Targeting Chimeras (PROTACs) has sparked a revolution in the field of biomedicine. PROTACs facilitate the degradation of specific target proteins by harnessing the ubiquitin-proteasome system (UPS) within cells, enabling precise modulation of disease-related proteins. This mechanism not only overcomes the limitations of traditional small-molecule drugs but also demonstrates significant advantages in targeting "undruggable" proteins.