Problem

Over 30,000 Americans are diagnosed every year with multiple myeloma (MM), a disease of clonal plasma cells which accumulate in the bone marrow. Despite several treatment options, MM is still incurable, and patients inevitably relapse and develop toxicities and functional decline. Novel therapeutics for the treatment of MM are urgently needed

Solution

Researchers at The Ohio State University have discovered that CD56 is abnormally expressed in over 70% of MM patients, where it promotes the activation of transcription factor CREB1. High levels of CREB1 are associated with elevated expression of HLA-E and inhibition of Natural Killer (NK) cell-mediated cytotoxicity, enabling MM cells to evade immune surveillance. Inhibition of CREB1 with the small molecule 666-15 restores NK cells activity against MM cell lines and patient samples, particularly in CD56-positive cases. Building on 666-15, four distinct PROteolysis-TArgeting Chimeras (PROTACs) were designed to directly eliminate CREB1 protein via the ubiquitin-proteasome system. All CREB1-PROTACs successfully induced dose-dependent CREB1 degradation and robust cell death. Treatment of MM cell lines with 50–500 nM of the lead compound #28 reduced viability and induced apoptosis while decreasing CREB1 downstream targets. Combination strategies with immunomodulatory drugs (IMiDs) demonstrated synergy between compound #28 and lenalidomide, pomalidomide, and iberdomide

Applications

Use of the CREB1-PROTACs for the treatment of MM, especially in patients overexpressing CD56, alone or in combination with approved therapies in myeloma

Advantages

• Proteasome-powered degradation: traditional inhibition of CREB1 can lead to off-target toxicity. PROTACs offer a more selective approach by leveraging the ubiquitin-proteasome system, which is highly active and therapeutically validated in MM
• Complete protein elimination: PROTACs induce proteasomal degradation of CREB1 rather than just inhibiting its activity, thus removing all functional roles of CREB1
• Persistent downregulation of CREB1: a single PROTAC molecule can degrade multiple CREB1 proteins, enabling lower doses and a more sustained suppression of CREB1-driven transcriptional programs even after drug clearance
• Overcoming drug resistance: small-molecule inhibitors that bind to an active site often fail when CREB1 undergoes mutations or conformational changes, while PROTACs require only an anchoring point on the protein, reducing resistance risk
• Combinations therapy: CREB1 inhibition can potentially enhance the effectiveness of IMiDs by blocking HLA-E–driven immune evasion

Seeking opportunities for out-licensing and collaboration