Abstract LB-303: Substrate-mimetic covalent inhibitor of MALT1 is most effective against CARD11 mutant ABC-DLBCL
Authors: Fontan Lorena , Scott David , Hatcher John , Qiao Qi , Us Ilkay , Casalena Gabriella , Bekkers Mariette , Philippar Ulrike , Durant Matthew , Chennamadhavuni Spandan , Wu Hao , Gray Nathaniel , Melnick Ari 
Published: July 2017

Abstract
Diffuse Large B-cell lymphoma is the most common subtype of B-cell non Hodgkin Lymphoma (B-NHL) representing 30% of all B-NHL. There are three molecular subtypes: germinal center B cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal B cell lymphoma (PMBL). Of those, Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL) represents a third of the patients and is characterized by constitutive NF-κB activity due to mutations in various proteins of the B-cell receptor (BCR) as well as Toll-like receptor (TLR) pathways. Mutations in the BCR pathway include: activating mutations of CD79A/B (20% of ABC-DLBCLs) and CARD11 (10%) and deletion or inactivating mutation of A20 (20-30%). In the TLR pathway, MYD88 is mutated in 37% of ABC-DLBCL patients. Given this scenario, numerous therapeutic strategies targeting proteins signaling downstream of the BCR pathway have been proposed for ABC-DLBCL -including inhibitors targeting kinases SYK, BTK, PI3K, PKC, MAPKs and AKT or the protease MALT1. MALT1 inhibition provides advantages to other targets because it is downstream of most of the BCR pathway mutations present in patients, including CARD11. Patients with CARD11 mutations do not respond to BTK inhibitors. However, none of the MALT1 inhibitors reported to date are good candidates for clinical use.
Here we report a new class of substrate mimetic MALT1 inhibitors based on Z-VRPR-fmk. Our lead compound, SCM-02-138 displayed nanomolar potency in biochemical and cellular MALT1 protease reporter assays. Crystallography shows covalent binding of the compound to MALT1 active site Cys residue. SCM-02-138 was highly selective for MALT1 and showed over 100-fold differential killing in sensitive vs resistant cell lines. MALT1 inhibition was most effective in CARD11 mutant cells. SCM-02-138 was active in vivo, as assessed by hIL10 inhibition in xenografted models of ABC-DLBCL cell lines. Moreover it was effective against ABC-DLBCL xenografts and PDX DLBCL ex vivo. Combination of SCM-02-138 with other BCR inhibitors revealed PI3K delta inhibition as the most synergistic combination. Combination of SCM-02-138 and CAL-101 potentiated both proliferation inhibition and apoptosis.
In summary, we have developed a new class of MALT1 peptidic inhibitor characterized by nanomolar potency, irreversibility and high specificity. This inhibitor will be particularly useful against CARD11 mutant ABC-DLBCL, which are resistant to BTK inhibitors.
Citation Format: Lorena Fontan, David Scott, John Hatcher, Qi Qiao, Ilkay Us, Gabriella Casalena, Mariette Bekkers, Ulrike Philippar, Matthew Durant, Spandan Chennamadhavuni, Hao Wu, Nathaniel Gray, Ari Melnick. Substrate-mimetic covalent inhibitor of MALT1 is most effective against CARD11 mutant ABC-DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-303. doi:10.1158/1538-7445.AM2017-LB-303