BTX-1188, a first-in-class dual degrader of GSPT1 and IKZF1/3, for treatment of acute myeloid leukemia (AML) and solid tumors.

7025 Background: BTX-1188 is a first-in-class oral molecular glue that degrades GSPT1 and IKZF1/3 and is currently in phase 1 clinical trials for treatment of hematologic and solid malignancies. Targeted protein degradation of cereblon neosubstrates is clinically validated in the treatment (tx) of hematologic malignancies (Lu 2014, Zou 2020). Methods: Cell viability in BTX-1188-treated cells and patient samples was measured by CellTiter-Glo 2.0 assay (Promega). Substrate degradation and apoptosis profiles were analyzed by immunoblots of protein lysates from cells treated with DMSO or BTX-1188. Vehicle, or 30 or 40 mg/kg IP BTX-1188, was used in athymic nude mice AML xenograft models. Results: BTX-1188 is a rapid, deep, and potent degrader of GSPT1 and IKZF1/3 and inhibitor of Myc in several cancer cell lines (Table). Proteomics and immunoblot analysis of AML cell line, MV-4-11, shows significant degradation of GSPT1 and IKZF1 after 2 h tx with 100 nM BTX-1188 ( P<1x10 -5 ) and 6 h tx with 3 nM BTX-1188 (>90% of GSPT1), respectively, indicating rapid and potent neosubstrate degradation. BTX-1188 also durably degrades GSPT1 where tx with 30 nM for 6 h followed by washout maintains significantly lower levels of GSPT1 and sustained apoptosis for up to 24 h. Owing to IKZF1/3 degradation, BTX-1188 has immunomodulatory properties as seen by inhibition of proinflammatory cytokines (IL-1β, IL-6, TNFα) and induction of IL-2 by LPS and αCD3-stimulated PBMCs, respectively. This approach is expected to improve clinical outcomes and reduce toxicities associated with pure GSPT1 degradation (CC-90009), thus expanding the therapeutic window of BTX-1188. Functionally, BTX-1188 is cytotoxic in various cancer cell lines such as Myc-driven lines (IC 50 range: 0.5-10 nM) and primary human AML patient samples (IC 50 range: 0.4-1.5 nM), including relapsed/refractory-, cytarabine- and venetoclax-resistant samples. The durability of GSPT1 degradation and sustained apoptosis in response to BTX-1188 tx is further reflected in in vivo efficacy models where daily or intermittent dosing of BTX-1188 results in potent and sustained antitumor activity. Conclusions: These preclinical data show that BTX-1188 is a promising drug candidate for AML and other tumor types. Its immunomodulatory properties owing to IKZF1/3 degradation may prevent systemic inflammatory dose-limiting toxicities associated with pure GSPT1 degradation (Uy 2019). BTX-1188 has entered phase 1 clinical studies for advanced solid tumors and AML. DC 50 (nM) or inhibitory concentration (nM) of BTX-1188 at 6 h of Tx. [Table: see text]