Enhanced Targeted Protein Degradation with SP-3164: Efficacy and Pharmacological Insights in Lymphoma Models

Targeted protein degradation (TPD) is gaining attention due to its advantages over traditional treatments, with SP-3164 being a promising oral next-generation agent anticipated to enter clinical trials in 2023. This compound binds to cereblon (CRBN), part of the CRL4 E3 ligase complex, leading to the ubiquitination and degradation of certain proteins like Ikaros and Aiolos. While most CRBN-binding molecules, including SP-3164, have a chiral structure with (S)- and (R)-enantiomers, the (S)-form is typically more effective. However, these enantiomers can interconvert, complicating the development of a pure form. SP-3164 utilizes deuterium to stabilize the (S)-enantiomer, potentially enhancing therapeutic efficacy compared to avadomide.

Our research compared SP-3164 to avadomide and SP-3165, a deuterium-stabilized (R)-enantiomer, and lenalidomide. We found that SP-3164 has a higher binding affinity to CRBN and induces more IKZF1 degradation in diffuse large B cell lymphoma (DLBCL) cell lines than avadomide or lenalidomide. The (R)-enantiomer, SP-3165, showed no significant IKZF1 depletion.

Pharmacokinetic studies in mice indicated that SP-3164 and SP-3165 have a longer exposure time and a shorter elimination half-life than avadomide, suggesting lower clinical doses and flexible dosing for SP-3164. In vivo testing in a mouse xenograft model of lymphoma showed that SP-3164 significantly outperformed lenalidomide in tumor growth inhibition. SP-3164 and avadomide had similar effects at comparable dosages, while SP-3165 had no significant anti-cancer impact due to its lack of CRBN binding.

The study concludes that SP-3164 is a novel CRBN-binding agent with superior therapeutic properties. It demonstrates high IKZF1 degradation efficiency and significant anti-cancer activity as a monotherapy in a lymphoma mouse model. Further research will assess SP-3164's efficacy and explore potential combinations for clinical development in DLBCL and other non-Hodgkin's lymphomas.