Molecular Glues Clinical Trial Pipeline Appears Robust With 10+ Key Pharma Companies Actively Working in the Therapeutics Segment | DelveInsight
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Key Takeaways from the Molecular Glues Competitive Landscape Report
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Molecular Glues Overview
Molecular glues are a novel class of small molecules that facilitate the interaction between proteins, leading to the degradation or modulation of target proteins that are typically difficult to drug. Unlike traditional inhibitors that block active sites of enzymes, molecular glues work by binding to two different proteins, often an E3 ubiquitin ligase and a target protein, bringing them into close proximity. This interaction results in the ubiquitination and subsequent proteasomal degradation of the target protein. The mechanism offers a unique therapeutic approach, particularly in oncology, where it can selectively degrade proteins essential for cancer cell survival. The specificity and efficacy of molecular glues have shown promise in preclinical and clinical studies, indicating their potential to address previously "undruggable" targets.
The discovery and development of molecular glues involve sophisticated techniques in chemical biology and proteomics. Researchers use high-throughput screening and structure-based drug design to identify compounds that can act as molecular glues. One of the most well-known examples is thalidomide and its derivatives, which act as molecular glue by promoting the degradation of specific transcription factors. The field is rapidly evolving, with ongoing research aimed at expanding the repertoire of targetable proteins and improving the specificity and potency of these compounds. As our understanding of protein-protein interactions and the ubiquitin-proteasome system deepens, molecular glues are poised to become a transformative modality in the treatment of various diseases.
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Molecular Glues Pipeline Analysis: Drug Profile
Golcadomide : Bristol Myers Squibb
Golcadomide (CC-99282) is an oral molecular glue that promotes degradation of IKZF1/3 transcription factors (Ikaros/Aiolos) by engaging the cereblon E3 ubiquitin ligase complex. Structurally golcadomide is a novel thalidomide analogue (known as a CELMoD/cereblon E3 ligase modulator). It has immunomodulatory actions, with enhanced antiproliferative and proapoptotic activities. Currently, Golcadomide is in Phase III stage of development for the treatment of B-cell Lymphoma.
RMC 6291: Revolution Medicines, Inc.
RMC-6291 is an orally active, covalent inhibitor targeting KRAS G12C(ON). It forms a tri-complex in tumor cells between KRAS G12C(ON) and cyclophilin A (CypA), thereby preventing KRAS G12C(ON) from signaling through steric hindrance of RAS effector binding. This inhibition blocks ERK signaling and induces apoptosis in KRAS G12C-mutant H358 cells. Additionally, RMC-6291 effectively inhibits the proliferation of KRAS G12C mutant cells, with a median IC50 of 0.11 nM. Currently, RMC-6291 is in Phase I/II stage of development for the treatment of Solid tumors including NSCLC and SCLC.
NST-628: Nested Therapeutics
NST-628 is a fully brain-penetrant, mechanistically novel non-degrading molecular glue that targets multiple nodes in the RAS/MAPK pathway. NST-628 was developed based on Nested's proprietary structural insights of how signaling complexes form and function in cancer and addresses common pitfalls of other MAPK-targeted compounds, which remain unable to circumvent the risk of resistance via signaling pathway reactivation. It is currently being evaluated in Phase I for the treatment of Solid tumors.
A snapshot of the Molecular Glues Pipeline Drugs mentioned in the report:
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Scope of the Molecular Glues Competitive Landscape Report
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