Abstract 832P
Background
MALT1 plays a key role in antigen receptor signalling and preclinical data indicate that MALT1 protease inhibition may have benefit in tumours with dysregulated NF-κB signalling, including activated B-cell-diffuse large B-cell lymphoma (ABC-DLBCL). MALT1 inhibitors are in clinical development as monotherapies and in combination with other agnets for the treatment of oncology and haematology indications, including lymphoma.
Methods
EXS73565 (‘565) was designed using generative design, machine learning and molecular dynamics approaches. The compound was characterised in MALT1 protease assays and DLBCL functional studies. In vivo efficacy of ‘565 was assessed in mouse xenograft models, alone and in combination with the BTK inhibitor ibrutinib. Profiling of ‘565 was undertaken in a range of selectivity and preclinical studies.
Results
‘565 is a potent and selective allosteric inhibitor of the MALT1 protease and inhibits the production of IL-10 and proliferation of DLBCL cells. In ABC-DLBCL xenograft studies, ‘565 demonstrated significant tumour growth inhibition. Tumour target engagement was demonstrated through measurement of the MALT1 protease target, RelB, and effects on NF-κB target genes. In an ABC-DLBCL xenograft model with low sensitivity to single-agent MALT1 and BTK inhibition in vivo, combining ‘565 and ibrutinib provided significant synergistic efficacy. Evaluation of ‘565 showed limited activity against CYP450 enzymes, hepatic and renal transporters. Notably, ‘565 avoids inhibition of UGT1A1 (an enzyme involved in metabolising bilirubin and certain small molecule drugs) in comparison to some clinical stage MALT1 inhibitors which carry a high UGT1A1 inhibition risk.
Conclusions
We describe the characterisation of EXS73565, an allosteric inhibitor of MALT1 which is currently in IND/CTA-enabling studies. Importantly, we show that ‘565 exhibits a low drug-drug interaction and hyperbilirubinemia risk, offering the prospect of fully exploring the potential of MALT1 inhibition as a monotherapy and/or in combination with other targeted agents.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Exscientia.
Disclosure
M. Gooyit, S. Varzandeh, A. Gavard, S. Robinson, F. Breitgoff, A. Cooke, A. Bradley, M. Dominguez: Financial Interests, Personal, Stocks/Shares: Exscientia; Other, Personal, Full or part-time Employment: Exscientia. A. Payne: Financial Interests, Personal, Stocks/Shares: Exscientia; Non-Financial Interests, Personal, Full or part-time Employment: Exscientia. C. Carvalheda, D. Evans, S. Richards, P. Ray: Other, Personal, Full or part-time Employment: Exscientia. C. Radoux, J. Besnard: Other, Personal, Full or part-time Employment: Exscientia; Financial Interests, Personal, Stocks/Shares: Exscientia.
Resources from the same session
844P - Progression -free survival prediction of multiple myeloma patients in five European countries using machine learning models
Presenter: Maria Luisa Pleguezuelo Witte
Session: Poster session 18
845P - A machine learning based clinical platform for cancer subtyping and data integration in hematological malignancies
Presenter: Michelle Tang
Session: Poster session 18
846P - Artificial intelligence-driven identification of onco-hematology patients who may develop severe COVID-19
Presenter: Souad Assaad
Session: Poster session 18
847P - Fatal infections among leukemia patients
Presenter: Huijie Zhou
Session: Poster session 18
848P - Mortality after rasburicase vs allopurinol anti-hyperuricemia monotherapy in patients with liquid tumors
Presenter: Mitchell Cairo
Session: Poster session 18
849P - Long non-coding RNA signatures and their role in the progression of childhood T cell acute lymphoblastic leukemia
Presenter: Pankaj Sharma
Session: Poster session 18
850P - A zebrafish model of MYC-driven acute myeloid leukemia reveals that neutrophil resistance to oncogenic transformation depends on their ability to promote PP2A-mediated MYC proteasomal degradation
Presenter: Anna Maria Luciano
Session: Poster session 18
851P - Characterization of a zebrafish model of MYC-driven acute myeloid leukemia
Presenter: Anna Maria Luciano
Session: Poster session 18
852P - c-MAF-driven metabolic reprogramming mediates H3K27 hyperacetylation to regulate super enhancer-associated genes
Presenter: Phyllis SY Chong
Session: Poster session 18
946P - Sintilimab plus lenvatinib as conversion therapy in patients with unresectable hepatocellular carcinoma: A prospective, non-randomized, open-label, phase II, expansion cohort study
Presenter: Shichun Lu
Session: Poster session 18