Drug resistance is a major challenge in cancer therapy, often causing relapse after initial successful treatment. Exploring resistance mechanisms and developing new treatments are key goals in oncology. Several promising targets for anticancer drug development have been identified or are under active investigation. For instance, KRAS mutations are prevalent in pancreatic, colorectal, and lung cancers, driving uncontrolled cell proliferation. DNA damage repair (DDR) mechanisms normally maintain genomic stability by repairing DNA damage, but defects in DDR pathways can make cancer cells more susceptible to targeted therapies like PARP inhibitors. EGFR resistance is frequently observed in clinical settings, and the emerging field of antibody-drug conjugate (ADC) therapies is also encountering drug resistance challenges. Drug-resistant cell lines are valuable tools for studying these resistance mechanisms and discovering novel therapies.
KRAS molecular glue is an innovative small-molecule drug designed to target the KRAS mutant protein. It works by binding to cyclophilin A (CYPA) within the cell, thereby reshaping the surface of CYPA. This modification enables CYPA to bind with KRAS-GTP, forming a stable ternary complex. The formation of this complex effectively disrupts the interaction be- tween KRAS-GTP and its downstream effector proteins, ultimately inhibiting the oncogenic signaling pathways driven by KRAS.
ICE has developed a comprehensive screening and evaluation platform for KRAS molecular glues, which includes a series of biochemical and cellular-level assays. For example, the plat- form utilizes biochemical and biophysical methods for the screening of POI binders, detec- tion of KRAS(ON)/CypA/cRAF binary complexes, and KRAS(ON)/CypA ternary complexes. It also incorporates cell-based functional assays, such as 2D/3D cell proliferation and detection of ERK phosphorylation, a marker associated with signaling pathways. In addition, the plat- form offers p-ERK and 2D/3D panel assay. The table below summarizes and presents some of the data from ICE.
Fragment-based drug design (FBDD) has emerged as a powerful strategy in drug discovery, particularly for identifying novel scaffolds and binding sites for challenging targets. We have employed a combination of Spectral Shift and TR-FRET technologies to discover new molecular glue scaffolds. Our fragment library is diverse and includes a rich variety of E3 ligases from different species, providing a sustainable and versatile screening platform.
Induced proximity, which utilizes small molecules to facilitate an interaction between two proteins to harness natural biological pathways, represents a revolution in synthetic chemistry and drug discovery [1]. This area has gained significant clinical traction, with targeted protein degradation leading the way. One example is Molecular glue degraders (MGDs), which induce the proximity of target protein to E3 ubiquitin ligases, leading to target ubiquitination and degradation. The mechanism is different from traditional inhibitors in drug discovery and broaden the approach, especially for the target used to be considered "undruggable". MRT-6160, a first-in-class VAV1-directed MGDs currently in clinical phase I, showed the remarkable potential in Immunology and inflammatory diseases such as rheumatoid arthritis and colitis [2][3]. Current advancements highlight its ability to reduce proinflammatory cytokine production, inhibit pathogenic T cell polarization, and mitigate autoimmune responses.
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