How Small Molecules Are Transforming Drug Development

Small-molecule drugs are effective and thus most widely used. However, their applications are limited by their reliance on active high-affinity binding sites, restricting their target options. A breakthrough approach involves molecular glues, a novel class of small-molecule compounds capable of inducing protein-protein interactions. This opens avenues to target conventionally undruggable proteins, overcoming limitations seen in conventional small-molecule drugs. Molecular glues play a key role in targeted protein degradation (TPD) techniques, including ubiquitin-proteasome system-based approaches such as Proteolysis Targeting Chimeras (PROTACs) and Molecular Glue Degraders and recently emergent lysosome system-based techniques like Molecular Degraders of Extracellular proteins through the Asialoglycoprotein receptors (MoDE-As) and Macroautophagy Degradation Targeting Chimeras (MADTACs). These techniques enable an innovative targeted degradation strategy for prolonged inhibition of pathology-associated proteins. This review provides an overview of them, emphasizing the clinical potential of molecular glues and guiding the development of molecular-glue-mediated TPD techniques.

🚀 𝗕𝗿𝗲𝗮𝗸𝗶𝗻𝗴 𝗡𝗲𝘄 𝗚𝗿𝗼𝘂𝗻𝗱 𝗶𝗻 𝗗𝗿𝘂𝗴 𝗗𝗶𝘀𝗰𝗼𝘃𝗲𝗿𝘆! 🚀 Exciting advancements in targeting Ras-, Rho-, and Rab-family GTPases - key enzymes involved in transducing inter- and intra-cellular signals. These small GTPases have long been considered "undruggable" due to their high affinity for GTP and the lack of allosteric sites. However, new research from 𝗠𝗼𝗿𝘀𝘁𝗲𝗶𝗻 𝗲𝘁 𝗮𝗹. (𝟮𝟬𝟮𝟰) is changing that narrative by exploiting a conserved cryptic pocket in the Switch II region, unlocking opportunities for drug development beyond K-Ras. 🔬 𝗞𝗲𝘆 𝗛𝗶𝗴𝗵𝗹𝗶𝗴𝗵𝘁𝘀: • A druggable Switch II pocket was found across many GTPases, allowing small molecule inhibitors to bind effectively. • Inhibitors like sotorasib and divarasib, originally designed for K-Ras-driven cancers, demonstrated success in targeting GTPases like H-Ras, N-Ras, and Rab1A. • This study offers hope for new therapies targeting previously undruggable proteins, with potential implications in cancer treatment and diseases like RASopathies. 💡 𝗪𝗵𝘆 𝘁𝗵𝗶𝘀 𝗺𝗮𝘁𝘁𝗲𝗿𝘀: This breakthrough opens doors for broad-spectrum inhibitors and family-specific drugs, pushing forward the development of therapies for cancers and other diseases where GTPase mutations play a role. What was once considered undruggable is now within reach, setting the stage for a new era in precision medicine. 👉 The future of drug discovery just got a lot brighter! 🌟 #DrugDiscovery #GTPase #RasProteins #CancerResearch #Pharmaceuticals #Innovation #PrecisionMedicine https://lnkd.in/ekHkxppE

Want to understand how protein dynamics influence cellular signaling in #BRAF? The interaction between BRAF and MEK1 is a critical step in the RAF/MEK/ERK pathway, which regulates cell growth and survival. Dysregulation of this pathway is linked to many cancers. Mutations like BRAF V600E cause continuous activation of MEK1 and downstream signaling, driving uncontrolled cell proliferation. Targeting this interaction is a key strategy in #cancer research to disrupt aberrant signaling in BRAF-mutant cancers. So, how does a mutation in the activation loop of BRAF modulate the BRAF-MEK1 interaction? Wild-type BRAF, remains in a dynamic equilibrium between active and inactive states, with the inactive state being predominant. The inactive form interacts with MEK1 and forms an auto-inhibited complex with the 14-3-3 protein, which is key in the signaling pathway. The V600E mutation "allosterically induces a population shift" from the inactive state to the active state, leading to activation of MEK1 and downstream signaling, thereby driving uncontrolled cell proliferation. Imagine having this much prior information before launching a drug discovery campaign. One could design small molecules that shift the population from the active to the inactive state, leading to the development of selective therapeutics against the BRAF V600E mutation, which occurs in over 90% of all #melanoma. Indeed, small molecules like Vemurafenib and Dabrafenib have been designed to precisely shift the population, restoring the autoinhibited BRAF-MEK1 complex. This highlights the power of #protein dynamics and its role in cellular signaling. We are building a generalizable foundation model of protein dynamics at scale, which will elucidate how population shifts between multiple metastable states govern protein-protein interactions. This foundation model will provide unprecedented predictive power to design #precision #therapeutics that can be rapidly advanced to the clinic, impacting millions of lives. #AI #DrugDiscovery #StructuralBiology #ProteinDynamics #cancer #biotech