A patent review of MALT1 inhibitors (2013-present)

被引:22
作者
Hamp, Isabel [1 ,2 ]
O'Neill, Thomas J. [3 ]
Plettenburg, Oliver [1 ,2 ]
Krappmann, Daniel [1 ]
机构
[1] Helmholtz Zentrum Munchen, Inst Med Chem, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany
[2] Leibniz Univ Hannover, Ctr Biomol Drug Res BMWZ, Inst Organ Chem, Hannover, Germany
[3] Helmholtz Zentrum Munchen, Res Unit Cellular Signal Integrat, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany
关键词
MALT1; allosteric inhibition; autoimmunity; cancer immunotherapy; lymphoma; proteases; regulatory T cells; NF-KAPPA-B; T-CELL; PARACASPASE MALT1; ALLOSTERIC INHIBITORS; PROTEASE ACTIVITY; TARGETING BTK; ACTIVATION; CLEAVAGE; IBRUTINIB; MECHANISMS;
D O I
10.1080/13543776.2021.1951703
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Introduction MALT1 is the only human paracaspase, a protease with unique cleavage activity and substrate specificity. As a key regulator of immune responses, MALT1 has attracted attention as an immune modulatory target for the treatment of autoimmune/inflammatory diseases. Further, chronic MALT1 protease activation drives survival of lymphomas, suggesting that MALT1 is a suitable drug target for lymphoid malignancies. Recent studies have indicated that MALT1 inhibition impairs immune suppressive function of regulatory T cells in the tumor microenvironment, suggesting that MALT1 inhibitors may boost anti-tumor immunity in the treatment of solid cancers. Areas covered This review summarizes the literature on MALT1 patents and applications. We discuss the potential therapeutic uses for MALT1 inhibitors based on patents and scientific literature. Expert opinion There has been a steep increase in MALT1 inhibitor patents. Compounds with high selectivity and good bioavailability have been developed. An allosteric binding pocket is the preferred site for potent and selective MALT1 targeting. MALT1 inhibitors have moved to early clinical trials, but toxicological studies indicate that long-term MALT1 inhibition can disrupt immune homeostasis and lead to autoimmunity. Even though this poses risks, preventing immune suppression may favor the use of MALT1 inhibitors in cancer immunotherapies.
引用
收藏
页码:1079 / 1096
页数:18
相关论文
共 114 条
[1]   The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes [J].
Afonina, Inna S. ;
Van Nuffel, Elien ;
Baudelet, Griet ;
Driege, Yasmine ;
Kreike, Marja ;
Staal, Jens ;
Beyaert, Rudi .
EMBO REPORTS, 2016, 17 (06) :914-927
[2]  
Albertella M., 2018, Patent No. [WO2018141749A1, 2018141749]
[3]   Structure?activity relationship studies of 3-substituted pyrazoles as novel allosteric inhibitors of MALT1 protease [J].
Asaba, Ken Nunettsu ;
Adachi, Yohei ;
Tokumaru, Kazuyuki ;
Watanabe, Akira ;
Goto, Yasufumi ;
Aoki, Takumi .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2021, 41
[4]   MALT1 Auto-Proteolysis Is Essential for NF-κB-Dependent Gene Transcription in Activated Lymphocytes [J].
Baens, Mathijs ;
Bonsignore, Luca ;
Somers, Riet ;
Vanderheydt, Charlotte ;
Weeks, Stephen D. ;
Gunnarsson, Jenny ;
Nilsson, Ewa ;
Roth, Robert G. ;
Thome, Margot ;
Marynen, Peter .
PLOS ONE, 2014, 9 (08)
[5]   The T-cell fingerprint of MALT1 paracaspase revealed by selective inhibition [J].
Bardet, Maureen ;
Unterreiner, Adeline ;
Malinverni, Claire ;
Lafossas, Frederique ;
Vedrine, Corinne ;
Boesch, Danielle ;
Kolb, Yeter ;
Kaiser, Daniel ;
Gluck, Anton ;
Schneider, Martin A. ;
Katopodis, Andreas ;
Renatus, Martin ;
Simic, Oliver ;
Schlapbach, Achim ;
Quancard, Jean ;
Regnier, Catherine H. ;
Bold, Guido ;
Pissot-Soldermann, Carole ;
Carballido, Jose M. ;
Kovarik, Jiri ;
Calzascia, Thomas ;
Bornancin, Frederic .
IMMUNOLOGY AND CELL BIOLOGY, 2018, 96 (01) :81-99
[6]   MALT1 protease: equilibrating immunity versus tolerance [J].
Bertossi, Arianna ;
Krappmann, Daniel .
EMBO JOURNAL, 2014, 33 (23) :2740-2742
[7]   Deficiency of MALT1 Paracaspase Activity Results in Unbalanced Regulatory and Effector T and B Cell Responses Leading to Multiorgan Inflammation [J].
Bornancin, Frederic ;
Renner, Florian ;
Touil, Ratiba ;
Sic, Heiko ;
Kolb, Yeter ;
Touil-Allaoui, Ismahane ;
Rush, James S. ;
Smith, Paul A. ;
Bigaud, Marc ;
Junker-Walker, Ursula ;
Burkhart, Christoph ;
Dawson, Janet ;
Niwa, Satoru ;
Katopodis, Andreas ;
Nuesslein-Hildesheim, Barbara ;
Weckbecker, Gisbert ;
Zenke, Gerhard ;
Kinzel, Bernd ;
Traggiai, Elisabetta ;
Brenner, Dirk ;
Bruestle, Anne ;
Paul, Michael St. ;
Zamurovic, Natasa ;
Mccoy, Kathy D. ;
Rolink, Antonius ;
Regnier, Catherine H. ;
Mak, Tak W. ;
Ohashi, Pamela S. ;
Patel, Dhavalkumar D. ;
Calzascia, Thomas .
JOURNAL OF IMMUNOLOGY, 2015, 194 (08) :3723-3734
[8]   Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery [J].
Burslem, George M. ;
Crews, Craig M. .
CELL, 2020, 181 (01) :102-114
[9]   Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia [J].
Byrd, John C. ;
Furman, Richard R. ;
Coutre, Steven E. ;
Flinn, Ian W. ;
Burger, Jan A. ;
Blum, Kristie A. ;
Grant, Barbara ;
Sharman, Jeff P. ;
Coleman, Morton ;
Wierda, William G. ;
Jones, Jeffrey A. ;
Zhao, Weiqiang ;
Heerema, Nyla A. ;
Johnson, Amy J. ;
Sukbuntherng, Juthamas ;
Chang, Betty Y. ;
Clow, Fong ;
Hedrick, Eric ;
Buggy, Joseph J. ;
James, Danelle F. ;
O'Brien, Susan .
NEW ENGLAND JOURNAL OF MEDICINE, 2013, 369 (01) :32-42
[10]   T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-κB inhibitor A20 [J].
Coornaert, Beatrice ;
Baens, Mathijs ;
Heyninck, Karen ;
Bekaert, Tine ;
Haegman, Mira ;
Staal, Jens ;
Sun, Lijun ;
Chen, Zhijian J. ;
Marynen, Peter ;
Beyaert, Rudi .
NATURE IMMUNOLOGY, 2008, 9 (03) :263-271