Cracking the Undruggable Code: Top 10 Key Takeaways

Posted on by Sara Christenson

For decades, the concept of “undruggable” targets has presented one of the most significant challenges in drug discovery. At our recent virtual event, Illuminating New Frontiers: Cracking the Undruggable Code, leading researchers and industry experts gathered to showcase cutting-edge technologies and fresh perspectives that are expanding the boundaries of therapeutic development. Over three engaging days, participants explored groundbreaking advances in targeting RAS signaling, leveraging protein degradation and induced proximity strategies, and exploring RNA as a therapeutic target.

Target engagement of RAF dimer inhibitor LXH254 at RAF kinases, in complex with KRAS (blue). RAF inhibitor LXH254 engages BRAF or CRAF protomers (orange), but spares ARAF (red). Unoccupied ARAF is competent trigger downstream mitogenic signaling (lightning bolts). Red cells in the background are fluorescently labeled RAS proteins, expressed in live cells.

This event was more than just a scientific conference–it was a space for collaboration, where ideas were exchanged, complex research challenges addressed, and transformative solutions brought to light. Below, we’ve distilled the most compelling insights into 10 key takeaways, showcasing the innovations and breakthroughs paving the way for a future where every target is within reach, and no one is left without options.

Top Ten Key Takeaways:

  1. Advancements in Biological Models to Understand RAS Signaling: Researchers Marie Schwinn and Tommy Turbyville  showcased CRISPR knock-in protein tagging techniques to create advancing cell models and KRAS membrane interaction studies, revealing new insights into RAS/RAF protein interactions.
  2. MEK Inhibitor Breakthroughs: Professor Arvin Dar presented new studies revealing how protein interactions drive unique binding mechanisms and resistance factors—leveraging technologies like NanoBRET® Target Engagement to connect biochemical findings with cellular responses.
  3. Innovative High-Throughput Assays for Complex Targets: HyunHee Cho from Novartis Institutes of BioMedical Research described a recent drug discovery campaign featuring the pERK Lumit® Immunoassay Cellular System for high-throughput screening and determining rank order of molecules impacting RAS signaling.
  4. Kinase Inhibitor-Induced Degradation: Dr. Georg Winter highlighted new insights into how traditional kinase inhibitors can induce protein degradation, revealing that harnessing or supercharging native degradation pathways is key to their mechanism of action.
  5. Overcoming KRAS Resistance: Professor Fleur Furguson described research targeting the transcription factor ZBTB11 for degradation, demonstrating potential in overcoming resistance to KRAS inhibitors in pancreatic cancer cells, with a synthetic lethal effect when combined with KRAS inhibitors.
  6. PROTAC Optimization for Oral Delivery: Professor Zoran Rankovic described recent research demonstrating that optimizing both the CRBN warhead and linker is proving essential for enhancing compound stability and improving properties for successful oral delivery.
  7. Understanding molecular glue selectivity: Research Scientist Kristin Riching described research using ternary complex formation to better understand molecular glue selectivity, highlighting collaborative efforts to identify a selective CK1α degrader.
  8. Targeting “undruggable” transcription factors through RNA degradation: Professor Matt Disney presented breakthrough findings on the degradation of cMYC mRNA, demonstrating the potential of targeting RNA to reduce cancer-driving proteins.
  9. Innovative cell-based screening for RNA binders: Professor Amanda Garner’s lab is pioneering advanced assays that enable study of RNA-protein interactions in live cells, providing valuable insights for the development of RNA-targeted therapeutics.
  10. Leveraging machine learning for RNA-ligand discovery: Investigator Jay Schneekloth’s team utilized machine learning to generate an extensive dataset of RNA-ligand interactions, enhancing our ability to predict RNA binding properties and guide future screening efforts.

The future of drug discovery lies in reimagining what is possible, and Illuminating New Frontiers: Cracking the Undruggable Code brought that vision to life. From new strategies to tackle resistance in RAS therapies to breakthroughs in RNA-ligand discovery, the event offered fresh perspectives and practical insights to address some of the toughest challenges in the field.

If you missed the live event, there’s still time to catch up. Register for the on-demand sessions today to access all the presentations and discussions. Don’t miss your chance to explore transformative ideas and connect with a community of researchers and innovators reshaping the future of drug discovery.

Overlay text of "Illuminating New Frontiers: Cracking the Undruggable Code." Background Image: Target engagement of RAF dimer inhibitor LXH254 at RAF kinases, in complex with KRAS (blue). RAF inhibitor LXH254 engages BRAF or CRAF protomers (orange), but spares ARAF (red). Unoccupied ARAF is competent trigger downstream mitogenic signaling (lightning bolts). Red cells in the background are fluorescently labeled RAS proteins, expressed in live cells.
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Sara Christenson

Sara Christenson

YouTube Optimization & Social Media Intern at Promega Corporation
Sara is a Marketing Coordinator at Promega. She earned her B.S. in Life Sciences Communication and a certificate in Digital Studies at the University of Wisconsin-Madison.

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