Development of novel anti-leukemia agents targeting the menin-MLL interaction

混合血统白血病1(MLL1)基因染色体易位导致MLL表达 在影响儿童和成人的急性白血病中，约有10%发现了融合蛋白。病人 携带MLL融合的预后非常差，仅有约35%的五年存活率，这意味着需要 开发新的治疗方法。MLL融合蛋白保留了MLL的N-末端片段，而C- 末端部分被60个融合伙伴中的一个取代，导致各种MLL融合。重要的是，所有 MLL融合蛋白与多发性内分泌肿瘤1(MEN1)编码的蛋白Menin相互作用 基因，而脑膜素-MLL融合蛋白的相互作用对MLL融合的致癌活性至关重要。 白血病。事实上，薄荷素-MLL的相互作用已经在临床前模型中得到验证，是一种有价值的 MLL白血病新疗法开发的分子靶点。我们假设对大脑的抑制 小分子分子与Menin-MLL融合蛋白相互作用应逆转MLL融合的致癌活性 蛋白质和体内抑制MLL白血病的进展，为MLL白血病的靶向治疗提供了新的途径 病人。 为此，我们开发了脑膜素-MLL抑制剂的小分子抑制剂，它代表了 据报道，第一个小分子可以阻止这种蛋白质间的相互作用。这些化合物直接结合到 Menin位于MLL结合部位，并强烈抑制Menin与MLL的相互作用。我们大幅优化了这两项服务 这些化合物的效力和类药物特性，导致非常有效的薄荷素-MLL抑制剂(IC50和lt；15 NM，Kd&lt；10 NM)。在MLL白血病细胞中，这些化合物选择性地抑制增殖，诱导分化 并在纳摩尔浓度下调MLL融合靶基因的表达。重要的是，薄荷醇- 我们开发的MLL抑制剂(如MI-503、MI-463)在小鼠体内显著阻止白血病的进展 MLL白血病模型。在本项目中，我们将继续优化脑膜素-MLL抑制剂，以进一步提高 它们的效力和类似药物的特性，目标是开发出在体内具有非常强的体内效力的化合物 侵袭性MLL白血病模型，包括患者来源的异种移植(PDX)。我们还将研究最优 脑膜素-MLL抑制剂与选定的化疗和靶向药物的组合以确定最佳方案 用于未来临床研究的组合。此外，我们将调查抗药性是否会发展到 用薄荷素-MLL抑制剂治疗。这项工作应该会产生非常有效和选择性的脑膜素-MLL抑制剂 这可能为MLL白血病的治疗提供一种新的治疗途径。

Chromosomal translocations of the Mixed Lineage Leukemia 1 (MLL1) gene that result in expression of MLL fusion proteins are found in about 10% of acute leukemias affecting both children and adults. Patients harboring MLL fusions have very poor prognosis, with only ~35% five-year survival rate, implying the need for development of new therapies. The MLL fusion proteins retain the N-terminal fragment of MLL, while the C- terminal portion is replaced by one out of 60 fusion partners leading to a variety of MLL fusions. Importantly, all MLL fusion proteins interact with menin, a protein encoded by the Multiple Endocrine Neoplasia 1 (MEN1) gene, and the menin-MLL fusion protein interaction is critical to the oncogenic activity of MLL fusions in leukemia. Indeed, the menin-MLL interaction has been validated in the pre-clinical models as a valuable molecular target for development of new therapies for MLL leukemia. We hypothesize that inhibition of the menin-MLL fusion protein interaction by small molecules should reverse oncogenic activity of MLL fusion proteins and inhibit progression of MLL leukemia in vivo, resulting in a new targeted therapy for MLL leukemia patients. To this end we developed small molecule inhibitors of the menin-MLL inhibitors, which represent the first small molecules reported to block this protein-protein interaction. These compounds directly binding to menin at the MLL binding site and strongly inhibit the menin-MLL interaction. We substantially optimized both potency and drug-like properties of these compounds, resulting in very potent menin-MLL inhibitors (IC50 < 15 nM, Kd < 10 nM). In MLL leukemia cells, these compounds selectively inhibit proliferation, induce differentiation and downregulate expression of MLL fusion target genes at nanomolar concentrations. Importantly, the menin- MLL inhibitors we developed (e.g. MI-503, MI-463) markedly block progression of leukemia in vivo in mice models of MLL leukemia. In this project we will continue optimization of menin-MLL inhibitors to further improve their potency and drug-like properties with the goal to develop compounds with very strong in vivo efficacy in aggressive models of MLL leukemia, including patient derived xenografts (PDX). We will also study optimal combinations of menin-MLL inhibitors with selected chemotherapy and targeted agents to identify the best combinations for future clinical studies. Furthermore, we will investigate whether resistance develops to the treatment with menin-MLL inhibitors. This work should result in very potent and selective menin-MLL inhibitors that may provide a novel therapeutic approach for the treatment of MLL leukemia patients.