Anti-BTK monoclonal antibody, clone 8G23I5

The development of an expedient synthesis to GDC-0852 (1), a reversible BTK inhibitor drug candidate, is described. The key starting material tricyclic lactam 5 was prepared by an annulation reaction of unprotected piperidine-2-carbaldehyde HCl salt (20) and N-Boc piperidine-2,4-dione 21 in a safe and scalable manner. A highly selective Pd-catalyzed C-N coupling of lactam 5 and linker 2a, followed by Suzuki-Miyaura coupling to fragment 8 subsequently provided a direct and convergent access to the penultimate 17. A simple NaBH4 aldehyde reduction completed the synthesis to GDC-0852 (1) in high yield (54% over 3 steps from 5) and purity (99.0 A% HPLC). (C) 2020 Elsevier Ltd. All rights reserved.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive lymphomas exhibiting increased glucose uptake. However, some DLBCLs featuring relatively low F-18-fluorodeoxyglucose (F-18-FDG) uptake denoted by the maximum standardized uptake value (SUVmax) on PET/CT have been identified. The biologic correlates of such a heterogeneity have remained largely unknown. Herein, we immunohistochemically detected and found low FDG-avid DLBCL cases featuring lower expression of some key molecules involved in B-cell receptor (BCR) signaling (pSYK) and glucose metabolism (GLUT1 and HK2). Besides, BCR-deficient DLBCL xenografts were found displaying lower SUVmax and expressions of pSYK, GLUT1, and HK2. Further immunoblotting demonstrated expressions of GLUT1 and HK2 in BCR-dependent DLBCLs could be down-regulated by a chemical SYK inhibition, whereas the inhibitory effects were not observed in BCR-deficient tumors. These findings suggest low FDG-avid DLBCLs display a silent BCR signaling and PET/CT might be utilized to tailor the BCR signaling-inhibitory treatment.