Abstract 1879: Pyrazolopyrimidines as novel selective allosteric MALT1 inhibitors with in vivo activity in ABC-DLBCL
Authors: Weiss Andreas , Radimerski Thomas , Wyss Daniel , Andraos Rita , Buhles Alexandra , Sterker Dario , Quancard Jean , Pissot Carole , Simic Oliver , Bigaud Marc , Bornancin Frederic , Schlapbach Achim , Regnier Catherine , McSheehy Paul , Buchdunger Elisabeth , Wartmann Markus , Renatus Martin , Endres Ralf , Sellers William , Hofmann Francesco 
Published: August 2018

Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common histological subtype of Non-Hodgkin's lymphoma, comprising 30% to 40% of all newly diagnosed cases. DLBCL is a biologically and clinically diverse disease with more than a dozen subtypes classified by the World Health Organization (WHO). Gene expression profiling groups DLBCL into three molecular subtypes, named according to their cell of origin, and which include germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL and primary mediastinal B cell lymphoma (PMBL). The current standard of care (SoC) is R-CHOP chemo-immunotherapy. Although the SoC is curative in a substantial proportion of patients, 40% of patients, especially in the ABC-DLBCL subtype, do not achieve durable remissions and suffer from progressive disease. In ABC-DLBCL, recurrent mutations in the B-cell receptor (BCR) and Toll-like receptor (TLR) pathways lead to constitutive NF-κB signaling. Mutations in the BCR pathway include gain-of-function mutations of CD79A/B (~20%) and CARD11 (~10%), and loss-of-function mutations of A20 (~25%). In the TLR pathway, MYD88 is commonly mutated (~37%). In recent years, knowledge of these aberrantly regulated pathways and their underlying mutations guided the development and investigation of newer molecular targeted agents, e.g. BTK, SYK, PI3K, PKC and MALT1 inhibitors. Among these strategies, inhibition of MALT1 provides the advantage that it is downstream of most of the reported BCR pathway mutations, including CARD11 mutations, and most of the targeted kinases with respect to potentially emerging resistance. However, no MALT1 inhibitor is in the clinic until now.
Here, we report the identification of pyrazolopyrimidines as a new class of allosteric MALT1 inhibitors and their optimization for in vivo. The lead compound shows nanomolar potency in biochemical and cellular MALT1 protease reporter assays. In addition, pyrazolopyrimidines are highly selective for MALT1 and demonstrate differential cell killing of CARD11 mutant ABC-DLBCL cells vs control cells in proliferation assays. Furthermore, we demonstrate in vivo activity of pyrazolopyrimidines in CD79 and CARD11 mutant ABC-DLBCL xenograft models, with the lead compound causing regression in a CARD11 mutant xenograft model.
Citation Format: Andreas Weiss, Thomas Radimerski, Daniel Wyss, Rita Andraos, Alexandra Buhles, Dario Sterker, Jean Quancard, Carole Pissot, Oliver Simic, Marc Bigaud, Frederic Bornancin, Achim Schlapbach, Catherine Regnier, Paul McSheehy, Elisabeth Buchdunger, Markus Wartmann, Martin Renatus, Ralf Endres, William Sellers, Francesco Hofmann. Pyrazolopyrimidines as novel selective allosteric MALT1 inhibitors with in vivo activity in ABC-DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1879.