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.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
