Abstract PO-49: Discovery of JNJ-67856633: A novel, first-in-class MALT1 protease inhibitor for the treatment of B-cell lymphomas
| العنوان: | Abstract PO-49: Discovery of JNJ-67856633: A novel, first-in-class MALT1 protease inhibitor for the treatment of B-cell lymphomas |
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| المؤلفون: | Yann Abraham, Bart Petrus Anna Maria Jozef Medaer, Weimei Sun, Greet Vanhoof, Haopeng Rui, Yusri Elsayed, Sriram Balasubramanian, Ulrike Philippar, Marcello Gaudiano, Jan Willem Thuring, Jenna D. Goldberg, Tianbao Lu, Jennifer Smit, Peter J. Connolly, James P. Edwards, Max Cummings, Emanuele Trella, John Gerecitano, Nele Vloemans, Ricardo Attar, Tony Greway, Katarzyna Wnuk-Lipinska, Jan Linders, Kristof Kimpe, Amy J. Johnson, Jaqueline Bussolari, Bas-jan van der Leede, Luc Van Nuffel, Mariette Bekkers, Katie Amssoms |
| المصدر: | Blood Cancer Discovery. 1:PO-49 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, biology, Chemistry, CD3, General Medicine, medicine.disease, BCL10, Lymphoma, 03 medical and health sciences, Interleukin 10, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, hemic and lymphatic diseases, 030220 oncology & carcinogenesis, biology.protein, Cancer research, medicine, Bruton's tyrosine kinase, IL-2 receptor, Tyrosine kinase, B cell |
| الوصف: | Introduction: Constitutive activation of the classical nuclear factor kappa-light-chain-enhancer of activated B cells (NF κB) pathway is a clear driver of B-cell lymphomas, especially the aggressive activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key mediator of the classical NF-κB signaling pathway downstream of B-cell receptor and T-cell receptor. MALT1 possesses two functions: a scaffolding function to recruit NF-κB signaling proteins and a protease function to cleave and inactivate inhibitors of the NF-κB signaling pathway. Methods: Using a high-throughput screen followed by iterative structure-activity relationship (SAR) analyses, the MALT1 inhibitor JNJ-67856633 was identified. JNJ-67856633 was evaluated using biochemical, cellular in vitro, in vivo tumor efficacy and safety models. Results: JNJ-67856633 is a potent, selective, allosteric inhibitor of MALT1 protease activity as measured by biochemical assays or downstream cellular cytokine readouts (IL6/10) or direct MALT1 substrate cleavage (RelB, BCL10). The compound inhibits proliferation of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines bearing CD79b or CARD11 mutations as well as models mimicking resistance to covalent Bruton's tyrosine kinase (BTK) inhibitors. Furthermore, combination effects were observed in CD79b cellular ABC-DLBCL models when JNJ-67856633 was combined with a BTK inhibitor. JNJ-67856633 showed activity in organoid cultures derived from ABC-DLBCL patients. JNJ-67856633 leads to potent in vivo pharmacodynamic shutdown in CD79b- as well as CARD11-mutant ABC-DLBCL models as measured by serum IL10 or uncleaved BCL10 levels in tumors. JNJ-67856633 exhibits potent tumor growth inhibition in two human DLBCL xenograft models, OCI Ly3 and OCI Ly10. In addition, >5 patient-derived DLBCL xenografts were evaluated and activity in mutation selected models was observed. To address the role of MALT1 inhibition in T cells, primary human T cells derived from normal healthy volunteers were treated with JNJ-67856633 in vitro. Dose-dependent inhibition of the generation of Tregs (CD4+CD25+FoxP3+) following CD3/28 stimulation was observed upon treatment with JNJ-67856633, suggesting a potential immune-modulatory role of MALT1 inhibition. Conclusions: Phase 1 clinical trials assessing the safety and efficacy of JNJ-67856633 initiated in 2019. JNJ-67856633 is a combination partner for BTK inhibitors and a promising treatment option for BTKi-resistant tumors, with demonstrated preclinical activity in CARD11 mutant tumors. In addition to ABC-DLBCL, a MALT1 inhibitor is a promising treatment option for patients with CLL, MCL, WM, and FL whose tumors have been shown to be sensitive to inhibition of BTK. MALT lymphomas, characterized by MALT1 and BCL10 translocation, represent another attractive target for MALT1 inhibition. Citation Format: Ulrike Philippar, Tianbao Lu, Lorena Fontan, Nele Vloemans, Mariette Bekkers, Luc van Nuffel, Marcello Gaudiano, Katarzyna Wnuk-Lipinska, Bas-Jan Van Der Leede, Katie Amssoms, Kristof Kimpe, Bart Medaer, Tony Greway, Yann Abraham, Max Cummings, Emanuele Trella, Greet Vanhoof, Weimei Sun, Jan Willem Thuring, Peter Connolly, Haopeng Rui, Sriram Balasubramanian, John Gerecitano, Ari Melnick, Ricardo Attar. Discovery of JNJ-67856633: A novel, first-in-class MALT1 protease inhibitor for the treatment of B-cell lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-49. |
| تدمد: | 2643-3249 2643-3230 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::0e8109699ae1dad100496dfd36f4ec75 https://doi.org/10.1158/2643-3249.lymphoma20-po-49 |
| رقم الأكسشن: | edsair.doi...........0e8109699ae1dad100496dfd36f4ec75 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 26433249 26433230 |
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