Abstract 4036: NMS-0963 is a novel potent, selective and orally available Syk inhibitor with promising preclinical activity in diffuse large B-cell lymphoma

Abstract

Abstract The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies, such as Chronic Lymphocytic Leukaemia (CLL) and Non-Hodgkin’s Lymphomas (NHL) including Diffuse Large B-cell Lymphomas (DLBCL). Small molecule inhibitors of key signaling kinases involved in the BCR pathway, such as the Btk inhibitor ibrutinib and the PI3Kdelta inhibitor idelalisib, have already demonstrated significant clinical activity. Spleen tyrosine kinase (Syk) is a non-receptor cytoplasmic tyrosine kinase that plays a fundamental role in BCR signaling initiation thus representing an additional potential therapeutic target for the inhibition of the BCR pathway. Here, we report the discovery and characterization of NMS-0963, a novel potent, selective and orally available Syk inhibitor, identified through an integrated medicinal chemistry and rational design approach. NMS-0963 showed potent inhibitory effect on Syk in an in vitro biochemical assay and displayed a good selectivity profile on a broad panel of kinases. On-target potency was confirmed in a cell-based assay using BaF3 cells engineered to express constitutively activated Syk, showing potent inhibition of Syk activity resulting in antiproliferative effect with IC50s in the low nanomolar range. Effective inhibition of BCR-mediated signaling pathway was observed in DLBCL-derived cell lines. NMS-0963 showed favourable ADME profile and good in vivo pharmacokinetic profiles after oral administration in mouse, rat and dog. Furthermore, NMS-963 demonstrated striking in vivo efficacy in tumor models of CD79/Myd88 mutated DLBCL, superior to competitors. Together with a permissive preclinical safety profile, these results support a rational for clinical development of NMS-0963 in DLBCL. Citation Format: Grazia Saturno, Michele Modugno, Paolo Orsini, Giovanni Cervi, Laura Buffa, Ilaria Motto, Nilla Avanzi, Marisa Montemartini, Fabio Gasparri, Gemma Texido, Arturo Galvani, Antonella Isacchi. NMS-0963 is a novel potent, selective and orally available Syk inhibitor with promising preclinical activity in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4036.