SP-3164 ‘Molecular Glue’ Stops Growth In Lab-grown Cells, Mice

Salarius Pharmaceuticals' small molecule binds to cereblon better than avadomide

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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SP-3164, an investigational small molecule protein degrader, showed potential for improved anti-multiple myeloma activity over similar approved compounds.

That’s according to preclinical data from its developer Salarius Pharmaceuticals that showed SP-3164 triggered the death of lab-grown cancer cells and held back cancer growth in a mouse model of multiple myeloma, where it outperformed the approved treatments Revlimid (lenalidomide) and Pomalyst (pomalidomide).

“These initial data explain why we believe SP-3164 is so exciting, with the potential to make a positive difference in the treatment of hematologic [blood] cancers,” said David Arthur, Salarius’ CEO, in a press release.

The data were presented by Daniela Santiesteban, PhD, Salarius’ director of targeted protein degradation development, at the 5th Annual Targeted Protein Degradation Summit, Oct. 26 in Massachusetts. The presentation was titled “Development of SP-3164, a cereblon-binding molecular glue.”

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The company is undertaking the necessary studies to secure regulatory approval to conduct the first-in-human clinical trial with SP-3164, which is anticipated to enter the clinic in 2023.

“We are looking forward to … completing our Investigational New Drug (IND)-enabling studies, submitting the SP-3164 IND to the U.S. Food and Drug Administration in the first half of 2023 and beginning clinical trials shortly thereafter,” Arthur said.

Multiple myeloma is a cancer that occurs when abnormal white blood cells (called myeloma cells) build up in the bone marrow, the spongy tissue inside the bones where new blood cells are made. Treatments may help keep these cells under control and ease the symptoms of the disease.

Some therapies, called immunomodulatory treatments, are thought to work in a variety of ways, one way being by stopping the growth of myeloma cells.

E3 ubiquitin ligase is a protein that tags other proteins for degradation within cells. This helps them get rid of unwanted or poorly working proteins, and perhaps cancer-promoting proteins too. But these cancer-promoting proteins may not be within reach for E3 ubiquitin ligase.

Sticking to ‘molecular glue’ treatment

This is where “molecular glues” could play a part. These types of molecules bring cancer-promoting proteins close to the E3 ubiquitin ligase by sticking to them so they can get tagged for degradation.

SP-3164, a “molecular glue” or targeted protein degrader, is a more stable version of avadomide (also called CC-122), a small molecule that’s been shown to have anti-cancer activities. Because it’s more stable, SP-3164 may have “improved efficacy and safety compared to avadomide,” researchers wrote in their presentation.

Both SP-3164 and avadomide work by binding to cereblon, a component of the E3 ubiquitin ligase “tagging machine.” Upon binding to cereblon, SP-3164 will co-opt the E3 ubiquitin ligase to tag cancer-promoting proteins for degradation.

In the lab, SP-3164 was found to bind more potently to cereblon than avadomide. It also led to rapid degradation of IKZF1 (also known as Ikaros) and IKZF3 (also known as Aiolos), two proteins involved in the growth of multiple myeloma.

This translated into the death of lab-grown cancer cells from different types of lymphoma (a cancer that begins in white blood cells) and multiple myeloma. The effect was dose-dependent, which means that higher doses of SP-3164 resulted in more dead cells.

In mice, a single dose of SP-3164 was enough to reach higher peak (maximum) levels in the blood than a single dose of avadomide. Avadomide’s dose was double that of SP-3164, which, according to researchers, suggests an opportunity to use lower doses in the clinic.

The researchers then moved to an animal model wherein human myeloma cells were transferred into mice. Some mice were treated with an oral daily dose of SP-3164 (1.5 mg/kg), whereas others received either avadomide (3 mg/kg) or a placebo.

Greater cancer growth inhibition with SP-3164

Mice treated with SP-3164 exhibited significant tumor growth inhibition when compared to those on a placebo. Although not statistically significant, this trend was also observed compared to mice treated with avadomide.

In a similar experiment, SP-3164 given at a concentration of 1.5 mg/kg exhibited significantly higher tumor growth inhibition when compared to Revlimid and Pomalyst, two other immunomodulatory treatments given at a higher concentration of 3 mg/kg.

Given twice daily, at a dose of 0.75 mg/kg each time, SP-3164 resulted in significantly improved tumor growth inhibition when compared to a single daily dose of 1.5 mg/kg.

SP-3164’s effect was increased when administered with dexamethasone, a type of  glucocorticoid.

“Our near-term plans for SP-3164 include research in multiple blood cancers, additional pharmacokinetic and pharmacodynamic work to better understand potential clinical dosing advantages and additional studies to explore immuno-oncology effects and potential combinations for SP-3164,” Arthur said. Pharmacokinetics refers to SP-3164’s movement into, through, and out of the body, while pharmacodynamics refers to its effects in the body.

The company plans to release additional preclinical data at the upcoming American Society of Hematology annual meeting this month.