Abstract 524: SP-3164, a novel ikaros and aiolos molecular glue degrader with preclinical activity in non-Hodgkin lymphomas

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.524-524
• Main Authors: Santiesteban, Daniela Y., Duncan, Aundrietta D., Mirza, Nadeem Q., DeWitt, Sheila, Jacques, Vincent, Horrigan, Stephen, Iyer, Swaminathan P.
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-524

Background: Relapsed or refractory (R/R) non-Hodgkin lymphomas (NHLs) continue to be an area of high unmet need with patients seeking novel, chemotherapy-free options. One modality that has demonstrated success in NHLs is targeted protein degradation (TPD). Lenalidomide (LEN), a molecular glue degrader, is approved for treatment of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other NHLs. Avadomide (AVA), a next-generation molecular glue, showed compelling clinical NHL activity. Notably, because of rapid in vivo interconversion between the (R)- and (S)-enantiomers, both compounds have been developed as 1:1 mixtures of (S)- and (R)- enantiomers, despite only the (S)-enantiomer having the desired anticancer and immunomodulation activity. To overcome this issue, we used deuterium to lock the (S)-enantiomer of AVA in place, producing the new chemical entity, SP-3164. SP-3164 is a cereblon-binding molecular glue that selectively degrades Ikaros and Aiolos (I/A). We have previously shown that SP-3164 effects rapid and deep degradation of Ikaros as compared to LEN and AVA and demonstrates tumor growth inhibition (TGI) in vivo. Importantly, we also demonstrated that the (R)-enantiomer (SP-3165) does not cause Ikaros degradation and has minimal activity in vivo, but instead may show negative off target effects in certain models. Here, we continue to explore SP-3164’s activity in NHLs and demonstrate its potential therapeutic advantages. Results: We examined SP-3164’s ability to degrade Aiolos in comparison to LEN, AVA, and SP-3165 across several DLBCL cell lines (WSU-DLCL2, SU-DHL-5, SU-DHL-10, JVM-2 and U2932). SP-3164 (500 nM) caused significantly more Aiolos degradation than LEN (10 µM) and performed comparably or better than AVA (1 µM), while SP-3165 (500 nM) did not cause appreciable degradation. To further characterize SP-3164 and SP-3165, we used flow cytometry to distinguish their ability to induce apoptosis in NHL cells. Cells were treated with SP-3164 (1 µM, 10 µM) and SP-3165 (1 µM) for 72 hours. SP-3164 induced both early and late-stage apoptotic markers in a dose dependent manner, while SP-3165 did not induce apoptosis, corroborating it is the inactive enantiomer. In an in vivo model of FL (DOHH2), SP-3164 (7.5 mg/kg BID PO) showed significant antitumor compared to vehicle and the approved agent tazemetostat (300 mg/kg BID PO). The combination of SP-3164 and tazemetostat was synergistic resulting in more significant TGI than SP-3