Kamel Emadeldin M, Khadrawy Sally Mostafa, Allam Ahmed A, Ahmed Noha A, Alkhayl Faris F Aba, Lamsabhi Al Mokhtar
Chemistry Department, Faculty of Science, Beni-Suef University, Beni Suef, 62514, Egypt.
Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), 11623, Riyadh, Saudi Arabia.
Med Oncol. 2025 Jul 19;42(8):350. doi: 10.1007/s12032-025-02897-w.
The CARMA1-BCL10-MALT1 (CBM) complex plays a pivotal role in mediating antigen receptor-induced activation of NF-κB, a pathway critical for lymphocyte survival and proliferation. In aggressive lymphoid malignancies such as activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), oncogenic mutations drive constitutive CBM complex activation, leading to chronic NF-κB signaling and treatment resistance. Traditional therapeutic approaches have focused on inhibiting MALT1's protease activity; however, these strategies incompletely suppress CBM-driven signaling and may provoke immune-related toxicities by selectively impairing regulatory T cell function. Recent insights into the structural basis of CBM assembly have identified the BCL10-MALT1 interaction, particularly the hydrophobic groove between MALT1's Ig1-Ig2 domains, as a critical therapeutic target. Small-molecule inhibitors such as M1i-124 have demonstrated the ability to disrupt this interaction, leading to dual inhibition of MALT1's scaffolding and protease activities, destabilization of the CBM complex, and selective toxicity toward ABC-DLBCL cells. Preclinical studies show promising efficacy with broad suppression of NF-κB signaling and cytokine production while minimizing off-target effects. This review highlights the biological rationale, preclinical progress, and future directions for targeting the BCL10-MALT1 interface, outlining a transformative strategy for precision therapy in lymphoma and other CBM-dependent diseases.
CARMA1-BCL10-MALT1（CBM）复合物在介导抗原受体诱导的NF-κB激活中起关键作用，NF-κB信号通路对淋巴细胞的存活和增殖至关重要。在侵袭性淋巴恶性肿瘤中，如活化B细胞样弥漫性大B细胞淋巴瘤（ABC-DLBCL），致癌突变驱动CBM复合物的组成性激活，导致慢性NF-κB信号传导和治疗抗性。传统的治疗方法侧重于抑制MALT1的蛋白酶活性；然而，这些策略不能完全抑制CBM驱动的信号传导，并且可能通过选择性损害调节性T细胞功能引发免疫相关毒性。最近对CBM组装结构基础的深入了解已确定BCL10-MALT1相互作用，特别是MALT1的Ig1-Ig2结构域之间的疏水凹槽，是一个关键的治疗靶点。小分子抑制剂如M1i-124已证明能够破坏这种相互作用，导致对MALT1的支架和蛋白酶活性的双重抑制、CBM复合物的不稳定以及对ABC-DLBCL细胞的选择性毒性。临床前研究显示出有前景的疗效，可广泛抑制NF-κB信号传导和细胞因子产生，同时将脱靶效应降至最低。本综述强调了靶向BCL10-MALT1界面的生物学原理、临床前进展和未来方向，概述了淋巴瘤及其他CBM依赖性疾病精准治疗的变革性策略。
