Prof. Margot Thome, University of Lausanne; Dr Ming Zhang, University of Lausanne; Dr Barbara Saxty, LifeArc; Dr Sururat Adigun, LifeArc; Dr Lisa Hale, LifeArc
The paracaspase Malt1 is oncogenically activated in three types of B cell lymphomas that are difficult to treat: MALT lymphoma, activated B cell diffuse large B cell lymphoma (ABC DLBCL) and mantle cell lymphoma. Malt 1 a cysteine-dependent, arginine-directed protease that is essential for the initiation of adaptive immune responses. Peptide and pharmacological inhibition of Malt1 has been shown to inhibit the growth of ABC-DLBCL cell lines and small molecule inhibition using tool compounds against can halt the progression of ABC-DLBCL xenografts in vivo. Therefore Malt1 inhibitors could offer a new therapeutic option for these types of lymphoma that have a significant unmet medical need.
Because Malt1 is a key signaling component downstream of the B- and T-cell receptor, there are further potential applications for Malt1 inhibitors in immunosuppression, e.g. the treatment of autoimmune diseases, the prevention of graft rejection and the treatment of inflammatory conditions involving activated B- and T-cells, such as for example eczema or psoriasis. Use of Malt1 inhibitors in immunomodulation could have improved side effect profiles over currently used immunosuppressants such as cyclosporine.
We have developed novel screening assays and screened for new small molecule inhibitors of the paracaspase MALT1. We have shown that monoubiquitination of Malt1 is required for its proteolytic activity and generated a constitutively active Malt1-ubiquitin fusion protein. This allows screening for novel allosteric or active site reversible inhibitors under physiological conditions without the need for the addition of kosmotropic salts. We have currently identified novel compounds that inhibit Malt1 in vitro.
Diffuse large B cell lymphoma is clearly an area of high unmet medical need. Improved therapies are needed for all DLBCLs but most urgently for the activated B cell-like (ABC) subtype, which is the most aggressive and chemoresistant form of DLBCL and for which the survival rate is extremely poor. There are a number of large pharma companies who have therapeutic approaches in various stages of clinical trials for DLBCL and a MALT1 inhibitor has attractive partnering potential. In addition to their potential in cancer, Malt1 inhibitors could be broadly applicable to a number of other indications including inflammatory disease, autoimmune diseases such as multiple sclerosis and transplant rejection thus making Malt1 inhibitors even more commercially attractive.
Hit to lead.
No current IP
Jaworski M and Thome M. Cell. Mol. Life Sci. 2015, 73(3): 459-73
Duwel M et al. J. Immunol. 2009, 182(12): 7718-7728
Hailfinger S et al. PNAS 2011, 108(35): 14596-14601
Yu J et al. PNAS 2011, 108(52): 21004-21009
Pelzer C et al. Nat. Immunol. 2013, 14(4), 337-345