Cancer-Stem-Cell Phenotype-Guided Discovery of a Microbiota-Inspired Synthetic Compound Targeting NPM1 for Leukemia

The human microbiota
plays an important role in human health and
disease, through the secretion of metabolites that regulate key biological
functions. We propose that microbiota metabolites represent an unexplored
chemical space of small drug-like molecules in the search of new hits
for drug discovery. Here, we describe the generation of a set of complex
chemotypes inspired on selected microbiota metabolites, which have
been synthesized using asymmetric organocatalytic reactions. Following
a primary screening in CSC models, we identified the novel compound
UCM-13369 (4b) whose cytotoxicity was mediated by NPM1.
This protein is one of the most frequent mutations of AML, and NPM1-mutated
AML is recognized by the WHO as a distinct hematopoietic malignancy.
UCM-13369 inhibits NPM1 expression, downregulates the pathway associated
with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding
domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved
in the AML tumorological process. The new NPM1 inhibitor triggers
apoptosis in AML cell lines and primary cells from AML patients and
reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation.
The disclosed phenotype-guided discovery of UCM-13369, a novel small
molecule inspired on microbiota metabolites, confirms that CSC death
induced by NPM1 inhibition represents a promising therapeutic opportunity
for NPM1-mutated AML, a high-mortality disease.

人类微生物群系（human microbiota）通过分泌调控关键生物学功能的代谢物，在人类健康与疾病进程中发挥重要作用。我们提出，微生物群代谢物是新药发现过程中尚未被发掘的小型类药分子化学空间。本文报道了一系列基于精选微生物群代谢物设计的复杂化学型的构建，这类化学型通过不对称有机催化反应完成合成。在癌症干细胞（Cancer Stem Cell, CSC）模型中开展初步筛选后，我们发现了新型化合物UCM-13369（4b），其细胞毒性由核仁磷酸蛋白1（Nucleophosmin 1, NPM1）介导。该蛋白是急性髓系白血病（Acute Myeloid Leukemia, AML）最常见的突变靶点之一，而携带NPM1突变的AML已被世界卫生组织（World Health Organization, WHO）列为独立的造血系统恶性肿瘤亚型。UCM-13369可抑制NPM1的表达，下调与突变型NPM1 C+相关的信号通路，并特异性识别NPM1 C+的C端DNA结合结构域，阻断该过程中参与AML肿瘤发生的核质转位环节。这款新型NPM1抑制剂可诱导AML细胞系及AML患者原代细胞发生细胞凋亡（apoptosis），并在携带NPM1 C+突变的AML小鼠模型中降低肿瘤浸润程度。本研究通过表型导向策略发现了这款源自微生物群代谢物的新型小分子UCM-13369，证实通过抑制NPM1诱导癌症干细胞死亡，可为高致死性的NPM1突变型AML提供极具潜力的治疗途径。